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MAPK

Genetic Prioritization, Therapeutic Repositioning and Cross-Disease Comparisons Reveal Inflammatory Targets Tractable for Kidney Stone Disease

12 | Oct 09 2021

Hai Fang et al. provided the rich information of how to target innate immune pathways, with the potential of advancing immunotherapeutic strategies for nephrolithiasis. [Read the Full Post]

Dual Inhibition of Histone Deacetylases and the Mechanistic Target of Rapamycin Promotes Apoptosis in Cell Line Models of Uveal Melanoma

18 | Oct 08 2021

Ruchi P Patel et al. found that romidepsin in combination with mTOR inhibition could be an effective treatment strategy against uveal melanoma due in part to changes in apoptotic proteins. [Read the Full Post]

Regulation and function of AP-1 in insulinoma cells and pancreatic β-cells

19 | Oct 05 2021

Tobias M Backes et al. found that AP-1 controls an important function of pancreatic β-cells in vivo, the regulation of glucose homeostasis. [Read the Full Post]

circBTBD7 Promotes Immature Porcine Sertoli Cell Growth through Modulating miR-24-3p/ MAPK7 Axis to Inactivate p38 MAPK Signaling Pathway

41 | Sep 28 2021

Qiao Bian et al. expanded our knowledge of noncoding RNAs in porcine normal spermatogenesis through deciding the fate of Sertoli cells. [Read the Full Post]

Machine learning identifies molecular regulators and therapeutics for targeting SARS-CoV2-induced cytokine release

64 | Sep 22 2021

Marina Chan et al. proposed that agented targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, might represent an attractive therapeutic option for treating moderate to severe COVID-19. [Read the Full Post]

EGFR and ERK activation resists flavonoid quercetin-induced anticancer activities in human cervical cancer cells in vitro

70 | Sep 21 2021

Xin Chen et al.determined the role of EGFR and the underlying signaling pathways involved in the anti-cervical cancer malignant behavior induced by Que and identified the negative regulatory association. [Read the Full Post]

Effect of Dickkopf-1 (Dkk-1) and SP600125, a JNK Inhibitor, on Wnt Signaling in Canine Prostate Cancer Growth and Bone Metastases Wachiraphan Supsavhad 1 2, Bardes B Hassan 1 3,

214 | Sep 05 2021

Wachiraphan Supsavhad et al. showed that SP600125 had the potential to serve as an alternative adjuvant therapy in some early-stage PCa patients, especially those with high Dkk-1 expression. [Read the Full Post]

Immunotherapy in Hepatocellular Carcinoma

183 | Aug 27 2021

Claudia A M Fulgenzi et al. thought that in the absence of predictive biomarkers, choice of immunotherapy over kinase inhibitors would continue to remain an empirical exercise, guided by balancing anti-tumour efficacy with toxicity considerations in the individual patient. [Read the Full Post]

Interpretable deep recommender system model for prediction of kinase inhibitor efficacy across cancer cell lines

59 | Aug 11 2021

Krzysztof Koras et al. proposed a novel interpretability approach, which in addition to the set of modeled features consideres also the genes and processes outside of this set. [Read the Full Post]

Effects of combination treatment with transcranial magnetic stimulation and bone marrow mesenchymal stem cell transplantation or Raf inhibition on spinal cord injury in rats

50 | Aug 10 2021

Sining Feng et al. thought that compared with monotherapy, combination therapy displayed an improved therapeutic effect on SCI by further suppressing Raf/MEK/ERK signaling. [Read the Full Post]

Inhibition of TLR4 prevents hippocampal hypoxic-ischemic injury by regulating ferroptosis in neonatal rats

88 | Aug 05 2021

Kaiyi Zhu et al. demonstrated that the inhibition of TLR4-p38 MAPK signaling modulated HIBD- or OGD-induced ferroptosis in neuronal cells and might play a novel role in brain homeostasis. [Read the Full Post]

Identification of DNA-Repair-Related Five-Gene Signature to Predict Prognosis in Patients with Esophageal Cancer

102 | Jul 30 2021

Lin Wang et al. found that small-molecule drugs (trametinib, selumetinib, and refametinib) could help to improve patient survival. [Read the Full Post]

The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis

87 | Jul 30 2021

Dennis Kobelt et al. found that MAP kinase signaling was not linear leading to ERK activation, but branched at the level of MEK1. [Read the Full Post]

Outcome of COVID-19 infection in 50 multiple myeloma patients treated with novel drugs: single-center experience

205 | Jul 27 2021

Marta Krejci et al. found that the course of COVID-19 disease in MM pts was mostly moderate or serious with 56% of hospitalizations and 18% of deaths. [Read the Full Post]

Cordycepin inhibits inflammatory responses through suppression of ERK activation in zebrafish

93 | Jul 25 2021

Wei Liu et al. found that the important roles of cordycepin in inhibiting LPS and injury-induced inflammation. [Read the Full Post]

Targeting ERK combined with apatinib may be a promising therapeutic strategy for treating oral squamous cell carcinoma

80 | Jul 14 2021

Tong-Chao Zhao et al. suggested that the combination of apatinib and SCH772984 was a potent OSCC therapy. [Read the Full Post]

Effective treatment of a BRAF V600E-mutant epithelioid glioblastoma patient by vemurafenib: a case report

74 | Jul 13 2021

Zhiying Lin et al. found that the use of BRAF inhibitors combined with inhibitors of these seven genes may be a useful remedial treatment option. [Read the Full Post]

Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600 mut melanoma patients

100 | Jul 02 2021

M Raynal et al. thought that monitoring PCD and PCT alone was unlikely to be useful in assessing response to treatment. [Read the Full Post]

The KRAS G12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy

130 | Jun 22 2021

David M Briere et al. demonstrated KRAS inhibition reversed an immunosuppressive tumor microenvironment and sensitized tumors to CIT through multiple mechanisms. [Read the Full Post]

Flurbiprofen as a biphenyl scaffold for the design of small molecules binding to PD-L1 protein dimer

144 | Jun 20 2021

Christian Bailly et al. found that the longer FLB derivative HCT1026 appeard as a suitable binder of the PD-L1 dimer, sliding well along the BMS binding cavity. [Read the Full Post]

YAP/TAZ suppress drug penetration into hepatocellular carcinoma via stromal activation

208 | Jun 15 2021

Kyungjoo Cho et al. indicated that drug delivery into liver cancer was impaired by YAP/TAZ signaling in tumor cells and subsequent activation of stroma by the signaling. [Read the Full Post]

Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study

111 | Jun 14 2021

Vivek Subbiah et al. found that Pralsetinib was a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. [Read the Full Post]

Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study

71 | Jun 13 2021

Katharina C Kähler et al. found that favorable therapy outcome upon vemurafenib plus cobimetinib. [Read the Full Post]

83JAK-STAT inhibition mediates romidepsin and mechlorethamine synergism in Cutaneous T-cell Lymphoma

52 | Jun 07 2021

Jose R Cortes et al. found a role for romidepsin plus mechlorethamine in combination in the treatment of CTCL and uncovered a previously unrecognized role for JAK-STAT signaling in the response to romidepsin and romidepsin-based combination therapies in SS. [Read the Full Post]

Hypoxia induces chemoresistance of esophageal cancer cells to cisplatin through regulating the lncRNA-EMS/miR-758-3p/WTAP axis

72 | Jun 04 2021

Zi-Jiang Zhu et al. uncovered a critical lncRNA-EMS/miR-758-3p/WTAP axis in regulating hypoxia-mediated drug resistance to cisplatin in EC. [Read the Full Post]

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours

179 | Jun 02 2021

Mark R Middleton et al. found that Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. [Read the Full Post]

ALK-negative lung inflammatory myofibroblastic tumor in a young adult: A case report and literature review of molecular alterations

207 | May 24 2021

Silvia Angela Debonis et al. thought that although there was no standard of care for the treatment of IMT, identifying genomic alterations could help to redefine the management of patients with negative-ALK disease. [Read the Full Post]

Thyroglobulin as a negative marker for malignancy in canine and human breast tumors

138 | May 19 2021

Sung-Hyun Hwang et al. found that Tg could be a negative indicator of malignancy in canine and human breast neoplasia. [Read the Full Post]

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy

112 | May 17 2021

Matthew J McConnell et al. thought that COVID-19 was associated with coagulopathy and endotheliopathy in the liver endothelium driven by IL-6 trans-signaling, a possible mechanism of liver injury. [Read the Full Post]

AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status

65 | Apr 29 2021

Rui Ma et al. found that the BRAF inhibitor AZ304 had broad spectrum antitumour activity, which was significantly enhanced by combination with Cetuximab in colorectal cancers in vitro and in vivo. [Read the Full Post]

Combined blockade of polo-like kinase and pan-RAF is effective against NRAS-mutant non-small cell lung cancer cells

48 | Apr 28 2021

Siyeon Park et al. found that human NRAS-mutant NSCLC cells were moderately sensitive to pan-RAF inhibitors. [Read the Full Post]

Mini review: The FDA-approved prescription drugs that target the MAPK signaling pathway in women with breast cancer

56 | Apr 28 2021

Fatemeh Khojasteh Poor et al. summarized the FDA-approved prescription drugs that targeted the MAPK signaling pathway in women with BC. [Read the Full Post]

LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors

56 | Apr 01 2021

Kelli-Ann Monaco et al. found that LXH254 was a novel RAF inhibitor, which was able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF. [Read the Full Post]

Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

62 | Mar 16 2021

Jing-Quan Wang et al. indicated that AZ-628 could be used in combination chemotherapy against ABCG2-mediated MDR in cancers. [Read the Full Post]

Differential Outcomes in Codon 12/13 and Codon 61 NRAS-Mutated Cancers in the Phase 2 NCI-MATCH Trial of Binimetinib in Patients with NRAS-Mutated Tumors

118 | Mar 07 2021

James M Cleary et al. thought that the observation of increased OS and PFS in codon 61 NRAS-mutated colorectal cancer patients merited further investigation. [Read the Full Post]

Mnk inhibitors: a patent review

238 | Mar 07 2021

Ahmed M Abdelaziz et al. provided a succinct review of the current state of development of pyridone-aminal-derived Mnk inhibitors through the analysis of relevant patent applications filed in the last 5 years. [Read the Full Post]

Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis

117 | Feb 23 2021

Shaohua Hou et al. suggested that ASK1 inhibitors could potentially be used as a therapeutic strategy for UC. [Read the Full Post]

Selonsertib, a potential drug for liver failure therapy by rescuing the mitochondrial dysfunction of macrophage via ASK1-JNK-DRP1 pathway

124 | Feb 22 2021

Guohua Lou et al. thought that selonsertib protected against LPS/GalN-induced ALF by attenuating JNK-mediated DRP1 mitochondrial translocation and then rescuing mitochondrial damage in macrophages and might have therapeutic potential for early ALF patients. [Read the Full Post]

Aloe-emodin relieves zidovudine-induced injury in neonatal rat ventricular myocytes by regulating the p90rsk/p-bad/bcl-2 signaling pathway

141 | Feb 11 2021

Wei Zhao et al. indicated that AE attenuated AZT-induced cardiomyocyte apoptosis by activating p90rsk. [Read the Full Post]

Inhibition of canine distemper virus replication by blocking pyrimidine nucleotide synthesis with A77 1726, the active metabolite of the anti-inflammatory drug leflunomide

84 | Jan 18 2021

Yao Li et al. suggested that the antiviral activity of A77 1726 against CDV was mediated by targeting pyrimidine nucleotide synthesis via inhibiting DHO-DHase activity and S6K1-mediated CAD activation. [Read the Full Post]

BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis

129 | Jan 06 2021

Kassandra Koumaki et al. showed that the BRAF paradox breakers PLX7904 and PLX8394 caused a more prolonged MAPK pathway inhibition and achieved a stronger blockage of proliferation and reduced viability than PLX4720, the sister compound of Vemurafenib. [Read the Full Post]

Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations

80 | Dec 31 2020

Marika Colombo et al. showed how the use of Birinapant could be a viable therapeutic option for patients with LKB1-mutated NSCLCs. [Read the Full Post]

Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma

78 | Dec 31 2020

J Biau et al. showed the phase 1 trial.This phase 1 trial was the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. [Read the Full Post]

A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors

100 | Dec 19 2020

Colin Weekes et al. thought that overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination. [Read the Full Post]

The Role of Syk in Inflammatory Response of Human Abdominal Aortic Aneurysm Tissue

247 | Dec 13 2020

Ryo Kanamoto et al. demonstrated an important role of Syk for IgG-dependent inflammatory response in human AAA. [Read the Full Post]

Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis

0 | Dec 12 2020

Alejandro Torres-Hernandez et al. found that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis. [Read the Full Post]

Physical Nature of Substituent Effects in XH/π Interactions

119 | Dec 09 2020

Jacob W G Bloom et al. showed that the impact of substituents on XH/π interactions depended strongly on the identity of the XH group, and the strength of these effects increased with increasing polarization of the XH bond. [Read the Full Post]

Scabronine G Methyl Ester Improves Memory-Related Behavior and Enhances Hippocampal Cell Proliferation and Long-Term Potentiation via the BDNF-CREB Pathway in Olfactory Bulbectomized Mice

151 | Dec 08 2020

Osamu Nakagawasai et al. revealed the potential of SG-ME in improving memory impairments by enhancing cell proliferation and LTP via activation of the BDNF/CREB signaling pathway in neurons. [Read the Full Post]

Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity

212 | Dec 07 2020

Sandeep Kumar et al. demonstrated that MLK3 played an important role in T cell biology, and targeting MLK3 could serve as a potential therapeutic intervention via increasing T cell cytotoxicity in cancer. [Read the Full Post]

An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development

166 | Nov 22 2020

Sunita Shankar et al. supported a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction was critical for PDAC progression. [Read the Full Post]

Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation

148 | Nov 13 2020

Chun-Hua Zhu et al. found that dexmedetomidine reduced the inflammatory response and epithelial cell death caused by VILI, via the activation of the ERK1/2 signaling pathway. [Read the Full Post]

Selective targeting of the αC and DFG-out pocket in p38 MAPK

131 | Nov 01 2020

Sandra Röhm et al. provided valuable insights into back-pocket interactions that were not addressed in SR-318 and it provided an alternative chemical tool with good cellular activity targeting also the p38 back pocket. [Read the Full Post]

Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia

0 | Nov 01 2020

Margherita Vieri et al. found that the identified combined action of nilotinib and MKC-8866 might represent a successful therapeutic strategy in high-risk Ph + ALL. [Read the Full Post]

NRAS Status Determines Sensitivity to SHP2 Inhibitor Combination Therapies Targeting the RAS-MAPK Pathway in Neuroblastoma

116 | Oct 04 2020

Ivette Valencia-Sama et al. suggested that conventional therapy-resistant, relapsed neuroblastoma might be effectively treated via combined inhibition of SHP2 and MEK or ERK of the RAS-MAPK pathway. [Read the Full Post]

Inhibition of the ERK/RSK kinase cascade limits Chlamydia trachomatis infection

123 | Oct 04 2020

Yaohua Xue et al. demonstrated not only that the ERK/RSK pathway played a critical role in Chlamydia infection, but also that these kinases had potential as targets for host-directed therapy against Chlamydia trachomatis. [Read the Full Post]

Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia

142 | Oct 02 2020

Margherita Vieri et al. found that the identified combined action of nilotinib and MKC-8866 might represent a successful therapeutic strategy in high-risk Ph + ALL. [Read the Full Post]

Transient Receptor Potential Ankyrin 1 (TRPA1) is Up-Regulated in Response to Lipopolysaccharide via P38/ Mitogen-Activated Protein Kinase (MAPK) in Dental Pulp Cells and Promotes Mineralization

147 | Sep 22 2020

Kento Tazawa et al. demonstrated that LPS stimulation induced TRPA1 via the NO-p38 MAPK signaling pathway and TRPA1 agonists promoted differentiation or mineralization of dental pulp cells. [Read the Full Post]

Flavonoids Restore Platinum Drug Sensitivity to Ovarian Carcinoma Cells in a Phospho-ERK1/2-Dependent Fashion

136 | Sep 15 2020

Yifat Koren Carmi et al. showed the potential of combining flavonoids with standard therapy to restore drug sensitivity to OC cells and overcomed TME-mediated platinum drug resistance. [Read the Full Post]

Proliferation of Vascular Smooth Muscle Cells under ox-LDL Is Regulated by Alismatis rhizoma Decoction via InhibitingERK1/2 and miR-17∼92a Cluster Activation

166 | Sep 14 2020

Julian Shen et al. provided the multitarget mechanisms for application of AD in the treatment of atherosclerosis. [Read the Full Post]

Anti-inflammatory Effect of AZD6244 on Acrolein-Induced Neuroinflammation

130 | Sep 10 2020

Wen-Chien Ho et al. suggested that ERK inhibition may be a neuroprotective target against acrolein-induced neuroinflammation in the CNS neurodegenerative diseases. [Read the Full Post]

GSK3β-Ikaros-ANXA4 signaling inhibits high-glucose-induced fibroblast migration

363 | Aug 19 2020

Youpei Wang et al. provided a new regulatory mechanism by which GSK3β negatively regulated human skin fibroblast cell migration. [Read the Full Post]

Selumetinib for plexiform neurofibromas in neurofibromatosis type 1: a single-institution experience

143 | Aug 09 2020

Vera Espírito Santo et al. showed that the drug was associated with clinical and radiological improvement. [Read the Full Post]

Proteasome Inhibitor PS-341 Effectively Blocks Infection by the Severe Fever with Thrombocytopenia Syndrome Virus

285 | Aug 07 2020

Sihua Liu et al. indicated that targeting of cellular interferon pathways and apoptosis during acute infection might serve as the bases of future therapeutics for the treatment of SFTSV infections. [Read the Full Post]

Regorafenib for Metastatic Colorectal Cancer: An Analysis of a Registry-Based Cohort of 555 Patients

254 | Aug 06 2020

Alena Novakova-Jiresova ETAL. found that regorafenib was a safe and active treatment option for a subgroup of patients with mCRC who were progressing after other systemic therapies and maintain good performance status. [Read the Full Post]

The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor

115 | Jul 19 2020

Nicolas Creusot et al. revealed that by using a panel of different cellular techniques it was possible to improve the assessment of hPXR agonist activity for new developed drugs. [Read the Full Post]

RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors

0 | Jul 18 2020

Xi Yuan et al. supported a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K-RAS-mutated cancers. [Read the Full Post]

A TLR7 agonist strengthens T and NK cell function during BRAF-targeted therapy in a preclinical melanoma model

119 | Jul 16 2020

Lydia Bellmann found that combined BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma. [Read the Full Post]

SB203580 Protects Against Inflammatory Response and Lung Injury in a Mouse Model of lipopolysaccharide‑induced Acute Lung Injury

250 | Jul 12 2020

Guirong Li et al. demonstrated that SB203580 protected against inflammatory responses and lung injury by inhibiting lung edema and downregulating proinflammatory mediators in LPS‑induced lung injury. [Read the Full Post]

MEK Inhibitors Combined With Programmed Cell death-1 Blockade Immunotherapy for Metastatic Uveal Melanoma: Is It Warranted?

154 | Jun 30 2020

Anais Zanella et al. highlighted the need to evaluate the safety and efficacy of new treatment options such as MEKi and anti-PD-1 for mUM. [Read the Full Post]

A New Compound With Increased Antitumor Activity by Cotargeting MEK and Pim-1

152 | Jun 30 2020

Yanan Li et al. uncovered a new MEK inhibitor KZ-02 with significantly enhanced antitumor activity by co-targeting MEK and Pim-1. [Read the Full Post]

Sequential Bortezomib and Temozolomide Treatment Promotes Immunological Responses in Glioblastoma Patients With Positive Clinical Outcomes: A Phase 1B Study

312 | Jun 25 2020

Mohummad A Rahman et al. found that Sequential BTZ + TMZ treatment was safe and promotes Th1-driven immunological responsed in selected patients with improved clinical outcomes (Clinicaltrial.gov (NCT03643549)). [Read the Full Post]

Anti-Inflammatory Properties of Chemical Probes in Human Whole Blood: Focus on Prostaglandin E 2 Production

143 | Jun 24 2020

Filip Bergqvist et al. deployed a semi-high throughput and robust methodology to investigate anti-inflammatory properties of new chemical probes. [Read the Full Post]

Overexpression of Fibroblast Growth factor-21 (FGF-21) Protects Mesenchymal Stem Cells Against Caspase-Dependent Apoptosis Induced by Oxidative Stress and Inflammation

431 | Jun 22 2020

Gabriel R Linares et al. provided compelling evidence that FGF-21 played a crucial role in protecting MSCs from apoptosis induced by oxidative stress and inflammation, and merited further investigation as a strategy for enhancing the therapeutic efficacy of stem cell-based therapies. [Read the Full Post]

RAF Dimer Inhibition Enhances the Antitumor Activity of MEK Inhibitors in K-RAS Mutant Tumors

278 | Jun 20 2020

Xi Yuan et al. supported a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K-RAS-mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K-RAS mutations and other MAPK pathway aberrations. [Read the Full Post]

Staurosporine and NEM Mainly Impair WNK-SPAK/OSR1 Mediated Phosphorylation of KCC2 and NKCC1

403 | Jun 18 2020

Jinwei Zhang et al. identified phospho-sites that are responsive to staurosporine or NEM application. [Read the Full Post]

HO-1 Downregulation Favors BRAF V600 Melanoma Cell Death Induced by Vemurafenib/PLX4032 and Increases NK Recognition

185 | Jun 13 2020

Anna L Furfaro et al. indicated that HO-1 downregulation can both improve the efficacy of Vemurafenib on melanoma cells and favor melanoma susceptibility to NK cell-mediated recognition and killing. [Read the Full Post]

Network Indirect Comparison of 3 BRAF + MEK Inhibitors for the Treatment of Advanced BRAF Mutated Melanoma

203 | Jun 12 2020

F Consoli et al. suggested a similar efficacy and a slightly different safety profile, related to specific molecular properties of the three different BRAF and MEK inhibitors currently approved in the management of advanced MM. [Read the Full Post]

Ocular Side Effects of Target Therapy and Immunotherapy in Patients With Cutaneous Malignant Melanoma

164 | Jun 07 2020

Jennifer Eikenberry et al. highlighted the frequency of ocular side effects in patients treated with target therapy and immunotherapy for CMM and showed that symptom resolution could be effectively achieved with proper ophthalmic care. [Read the Full Post]

Loss of HAT1 Expression Confers BRAFV600E Inhibitor Resistance to Melanoma Cells by Activating MAPK Signaling via IGF1R

176 | Jun 07 2020

Suresh Bugide et al. showed that the loss of HAT1 expression confered acquired BRAFi resistance by activating the MAPK signaling pathway via IGF1R. [Read the Full Post]

GSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation With Favorable Pharmacokinetic Properties for Sustained in Vivo Pathway Inhibition

0 | May 26 2020

Aidan G Gilmartin et al. found that GSK1120212 combineed high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical MEK inhibitors. [Read the Full Post]

Severe pyrexia from nivolumab-resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib.

0 | May 04 2020

Amagai R et al. suggested that pyrexia caused by BRAF/MEK inhibitors may possess a similar pathophysiology as that of AOSD. [Read the Full Post]

A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients With Advanced Cancer

178 | Apr 26 2020

Amita Patnaik et al. demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. [Read the Full Post]

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK With Antitumor Activity

163 | Apr 26 2020

Robert M Campbell et al. showed that LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer. [Read the Full Post]

TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer

192 | Mar 25 2020

Zhao B et al. showed accumulation of MEKi in the lysosomes of treated cells. [Read the Full Post]

A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors

190 | Mar 17 2020

Varga A et al. indicated that GDC-0994 had an acceptable safety profile and pharmacodynamic effects were observed by FDG-PET and in serial tumor biopsies. Single-agent activity was observed in 2 patients with BRAF-mutant colorectal cancer. [Read the Full Post]

Inhibitory effect of 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H - imidazole on HCMV DNA replication and permissive infection

175 | Mar 03 2020

Johnson RA et al. described FHPI as a novel anti-HCMV compound that inhibits synthesis/activation of cellular and/or viral factors required for initiation of HCMV DNA replication. [Read the Full Post]

T-cell death-associated gene 8 accelerates atherosclerosis by promoting vascular smooth muscle cell proliferation and migration

275 | Mar 02 2020

Chen LD et al. demonstrated that Tdag8 mediated phenotype transformation, proliferation and migration of VSMCs via the cAMP/PKA signaling pathway, thus partially contributing to atherosclerosis. [Read the Full Post]

URMC-099 Facilitates Amyloid-β Clearance in a Murine Model of Alzheimer's Disease

429 | Mar 01 2020

Tomomi Kiyota et al. indicated that URMC-099 facilitates Aβ clearance in the brain of APP/PS1 mice. The multifaceted immune modulatory and neuroprotective roles of URMC-099 make it an attractive candidate for ameliorating the course of AD. This is buttressed by removal of pathologic Aβ species and restoration of the brain's microenvironment during disease. [Read the Full Post]

Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study

189 | Feb 09 2020

Poprach A et al. found that the presence of skin toxicity is associated with improved OS and PFS in patients with mRCC treated with sunitinib. [Read the Full Post]

PD98059 protects the brain against mitochondrial-mediated apoptosis and autophagy in a cardiac arrest rat model

200 | Feb 03 2020

Zheng JH et al. showed that PD98059 decreased the openings of MPTP, CytC release, caspase3 activation, apoptotic indices, LC3-II, Beclin-1and increased P62. PD98059 also inhibited mitochondria-dependent apoptosis and the activity of autophagy in a dose-dependent manner in rat cerebral cortices at 24 h post-resuscitation. The generation of phosphorylated Drp1-616 was down-regulated accompanied by a decrease of TUNEL-positive cells and LC3 in dual immunostaining after PD98059 inhibited activation of ERK signaling pathway in a dose-dependent manner in rat cerebral cortices at 24 h post-resuscitation. [Read the Full Post]

The small molecule AZD6244 inhibits dengue virus replication in vitro and protects against lethal challenge in a mouse model

178 | Jan 30 2020

de Oliveira LC et al. demonstrated the potential of AZD6244 as a new therapeutic agent to treat DENV infection and possibly other flavivirus diseases. [Read the Full Post]

MTA1 promotes tumorigenesis and development of esophageal squamous cell carcinoma via activating the MEK/ERK/p90RSK signaling pathway

205 | Jan 30 2020

Nan P et al. found that MTA1 plays a pivotal oncogenic role in ESCC tumorigenesis and development through activating the MEK/ERK/p90RSK pathway. [Read the Full Post]

Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAFV600E by synergistically decreasing global trimethylation of H3K27

189 | Jan 29 2020

Fu H et al. found that tazemetostat combined with MAPKi enhances differentiation of PTC cells harbouring BRAFV600E through synergistically decreasing global trimethylation of H3K27, representing a novel differentiation strategy. [Read the Full Post]

Automobile exhaust-derived PM2.5 induces blood-testis barrier damage through ROS-MAPK-Nrf2 pathway in sertoli cells of rats

0 | Jan 19 2020

Liu B et al. indicated that PM2.5 derived from automobile exhaust causes oxidative stress, which in turn causes cellular apoptosis of SCs and damage of the blood-testis barrier, resulting male spermatogenesis dysfunction, in which ROS-MAPK-Nrf-2 pathways may play a key role. [Read the Full Post]

Clonorchis sinensis ESPs enhance the activation of hepatic stellate cells by a cross-talk of TLR4 and TGF-β/Smads Signaling pathway

173 | Jan 17 2020

Li B et al. demonstrated that activation of HSCs caused by CsESPs is mediated by a cross-talk between TLR4 and TGF-β/Smads signaling pathway, and may be provide a potential treatment strategy to interrupt the process of liver fibrosis caused by C. sinensis. [Read the Full Post]

Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma

212 | Jan 09 2020

Estrela JM et al. found that melanoma resistance is decreased if AKT and NF-κB signaling pathways are blocked. [Read the Full Post]

VCAM-1 Upregulation Contributes to Insensitivity of Vemurafenib in BRAF-Mutant Thyroid Cancer

216 | Jan 09 2020

Chen S et al. demonstrated that VCAM-1 is upregulated in thyroid cancer cells treated with vemurafenib and contributes to vemurafenib resistance in BRAF-mutant thyroid cancer cells. [Read the Full Post]

BIRB 796 has Distinctive Anti-inflammatory Effects on Different Cell Types

220 | Jan 07 2020

Ryoo S et al. suggested that the anti-inflammatory function of BIRB 796 depends on cell types. [Read the Full Post]

In vitro anti-osteoclastogenic activity of p38 inhibitor doramapimod via inhibiting migration of pre-osteoclasts and NFATc1 activity

0 | Jan 06 2020

Moon SH et al. suggested anti-osteoclastogenic activity of doramapimod via inhibiting migration/fusion of pre-osteoclasts and NFATc1 activity. [Read the Full Post]

Effects of pharmacogenetic variants on vemurafenib-related toxicities in patients with melanoma

183 | Dec 31 2019

Goey AK found that genetic variants in CYP3A4 and ABCB1 are associated with vemurafenib-associated toxicities. [Read the Full Post]

LKB1 deficiency renders non-small-cell lung cancer cells sensitive to ERK inhibitors.: ERK inhibitors in LKB1 mutated NSCLC

213 | Dec 11 2019

Caiola E et al. showed that ERK inhibitors are effective in LKB1 and LKB1/KRAS mutated tumors, thus offering a therapeutic strategy for this prognostically unfavorable subgroup of patients. Since ERK inhibitors are already in clinical development, our findings could be easily translatable to the clinic. Importantly, the lack of effect in cells expressing wild-type LKB1, predicts that treatment of LKB1 mutated tumors with ERK inhibitors should have a favorable toxicity profile. [Read the Full Post]

In Silico Screening Reveals Histone Deacetylase 7 and ERK1/2 as Potential Targets for Artemisinin Dimer and Artemisinin Dimer Hemisuccinate

205 | Dec 11 2019

Ishola AA et al. suggested that artemisinin dimer and artemisinin dimer hemisuccinate could be promising anticancer drug agents, with better therapeutic efficacy than ulixertinib and apicidin in the treatment of cancer via inhibition of HDAC7, ERK1 and ERK2. [Read the Full Post]

JNK-IN-8, a c-Jun N-terminal kinase inhibitor, improves functional recovery through suppressing neuroinflammation in ischemic stroke

286 | Dec 08 2019

Zheng J et al. demonstrated that JNK-IN-8 inhibits neuroinflammation and improved neurological function by inhibiting JNK/NF-κB and is a promising agent for the prevention of ischemic brain injury. [Read the Full Post]

SB202190 inhibits endothelial cell apoptosis via induction of autophagy and heme oxygenase-1

226 | Nov 29 2019

Schwartz M et al. opposed HO-1 to contribute to SB202190-mediated increases in metabolic activity and autophagy, respectively. [Read the Full Post]

U0126 attenuates ischemia/reperfusion-induced apoptosis and autophagy in myocardium through MEK/ERK/EGR-1 pathway

230 | Nov 20 2019

Wang A et al. suggested that U0126 may protect against H/R injury by preventing H/R-induced myocardium apoptosis and autophagy via the MEK/ERK/EGR-1 pathway, and may be a potential therapeutic approach for attenuating myocardial I/R injury. [Read the Full Post]

PK-PD modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 in A2058 xenografts

200 | Nov 20 2019

Choo EF et al. suggested that, based on minimal data, it is possible to predict the effects of various combinations preclinically and also assess the potential clinical efficacy of combinations using human pharmacokinetic inputs. [Read the Full Post]

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity

201 | Nov 05 2019

Bernstein A et al. found that Dual BRAF/MEK inhibitor therapy represents an exciting treatment option for patients with BRAF V600E primary brain tumors. In addition to greater efficacy than single-agent dabrafenib, this combination has the potential to mitigate cutaneous toxicity, one of the most common and concerning BRAF inhibitor-related adverse events. [Read the Full Post]

Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab

200 | Nov 04 2019

Moser JC et al. found that patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi. [Read the Full Post]

SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy

328 | Oct 30 2019

Zhang H et al. demonstrated that NRF2 is required for SP600125's protection against DN. SP600125 activates NRF2 possibly via inhibition of JNK-induced Keap1 expression. [Read the Full Post]

SB203580 inhibits epithelial-mesenchymal transition and pulmonary fibrosis in a rat silicosis model

244 | Oct 12 2019

Yan W et al. suggested that p38 MAPK/ZEB-1 (ZEB-2, Twist) pathway was involved at 7days after silica instillation and p38 MAPK was pivotal for EMT in silicosis fibrosis in rats. [Read the Full Post]

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma

305 | Sep 25 2019

Long GV et al. indicated that adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. [Read the Full Post]

Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex

250 | Sep 24 2019

Konermann S et al. demonstrated the potential of Cas9-based activators as a powerful genetic perturbation technology. [Read the Full Post]

Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas

242 | Sep 01 2019

Dombi E et al. suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. [Read the Full Post]

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study

217 | Sep 01 2019

Banerjee A et al. indicated that selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs. [Read the Full Post]

RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models

243 | Aug 29 2019

Yang H et al. indicated their findings offer evidence of the potent antitumor activity of RG7204 against melanomas harboring the mutant BRAF(V600E) gene. [Read the Full Post]

Inhibition of glioblastoma dispersal by the MEK inhibitor PD0325901

225 | Aug 21 2019

Shannon S et al. showed that PD0325901 significantly increases aggregate cohesion, stiffness, and viscosity but only when tumor cells have access to high concentrations of fibronectin. Treatment also results in reorganization of actin from cortical into stress fibers, in both 2D and 3D culture. Moreover, drug treatment localized pFAK at sites of cell-substratum adhesion. Collectively, these changes resulted in increased strength of substrate attachment and decreased motility, a decrease in aggregate dispersal velocity, and in a marked decrease in growth rate of both 2D and 3D cultures. [Read the Full Post]

Human primary liver cancer-derived organoid cultures for disease modeling and drug screening

262 | Aug 04 2019

Broutier L et al. demonstrated the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease. [Read the Full Post]

Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α

244 | Jul 26 2019

Qiu Y et al. indicated that miR-16/14-3-3η is involved in sorafenib resistance in HCC and that these two factors could be potential therapeutic targets and biomarkers for predicting the response to sorafenib treatment. [Read the Full Post]

GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition

353 | Jul 21 2019

Gilmartin AG et al. showed that GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical MEK inhibitors. [Read the Full Post]

A high-performance liquid chromatography-tandem mass spectrometry method for the determination of lifrafenib, a novel RAF kinase and EGFR inhibitor, in human plasma and urine and its application in clinical pharmacokinetic study

433 | Jul 01 2019

Yao X et al. showed robust and sensitive, it successfully fulfilled the requirement of clinical pharmacokinetic study of lifirafenib in Chinese patients with locally advanced or metastatic solid tumors. [Read the Full Post]

Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic

200 | Jun 28 2019

Ramurthy S et al. indicated that a structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials. [Read the Full Post]

A DSTYK mutation activates ERK1/2 signaling to promote intraspinal dissemination in a case of solitary fibrous tumor/hemangiopericytoma

293 | Jun 18 2019

Tang G et al. revealed the potential role of DSTYK mutation in the regulation of intraspinal metastasis of SFT/HPC, which might provide new biological insights into this rare disease. [Read the Full Post]

Trametinib Induces Neurofibroma Shrinkage and Enables Surgery

277 | Jun 11 2019

Vaassen P et al. suggested that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1. [Read the Full Post]

Regulation of cisplatin-resistant head and neck squamous cell carcinoma by the SRC/ETS-1 signaling pathway

228 | Jun 06 2019

Yang Z et al. demonstrated that the SRC/ETS-1 pathway plays a crucial role and could be a key therapeutic target in cisplatin-resistant HNSCC treatment. [Read the Full Post]

Differential effects of p38 MAP kinase inhibitors SB203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line

265 | Jun 05 2019

Düzgün ŞA et al. indicated the ERK1/2 phosphorylation level was not modified by low concentrations (1 or 5 µM) of SB202190 and SB203580; while a high concentration (50 µM) of both inhibitors caused significant reductions in the ERK1/2 phosphorylation. In addition, it was determined that both p38 MAPK inhibitors caused significant increases on the Ser15 phosphorylation of mutant p53 in MDA-MB-231 under these experimental conditions; while SB202190 was more potent than SB203580. [Read the Full Post]

Targeting ERK1/2 protein-serine/threonine kinases in human cancers

0 | May 29 2019

Roskoski R Jr indicated that Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors. These agents are effective against cell lines that are resistant to B-Raf and MEK1/2 inhibitor therapy. Although MK-8353 does not directly inhibit MEK1/2, it decreases the phosphorylation of ERK1/2 as well as the phosphorylation of RSK, an ERK1/2 substrate. The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway. [Read the Full Post]

A novel anti-melanoma SRC-family kinase inhibitor.

313 | May 24 2019

Halaban R suggested that the new compound could be used in the clinic as a substitute for, or in combination with MAPK inhibitors. [Read the Full Post]

Targeting ERK1/2 protein-serine/threonine kinases in human cancers

0 | May 23 2019

Roskoski R Jr showed that Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors. These agents are effective against cell lines that are resistant to B-Raf and MEK1/2 inhibitor therapy. Although MK-8353 does not directly inhibit MEK1/2, it decreases the phosphorylation of ERK1/2 as well as the phosphorylation of RSK, an ERK1/2 substrate. The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway. [Read the Full Post]

Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study

208 | May 16 2019

Long GV et al. demonstrated that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting. [Read the Full Post]

Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations

211 | May 15 2019

Greger JG et al. showed that NRAS and/or MEK mutations contribute to BRAF inhibitor resistance in vitro, and the combination of GSK2118436 and GSK1120212 overcomes this resistance. [Read the Full Post]

Simultaneous long-lasting regression of multiple nevi and melanoma metastases after ipilimumab therapy

284 | May 03 2019

Plaquevent M et al. suggested that a major regression of multiple nevi on ipilimumab might be associated with immunotherapy response. [Read the Full Post]

Vemurafenib Treatment of Pleomorphic Xanthoastrocytoma in a Child With Down Syndrome

262 | May 02 2019

Petruzzellis G et al. report the case of an 8-years-old child with DS that presented to our attention for neurological and endocrinological issues. [Read the Full Post]

Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells

219 | May 02 2019

Mito-CP-induced cell death was partially rescued by mortalin overexpression, suggesting that Mito-CP may inactivate a mechanism that requires mortalin function. These findings support the significance of mortalin and mitochondrial activity in a broad spectrum of thyroid cancer. [Read the Full Post]

Targeting ERK1/2 protein-serine/threonine kinases in human cancers

313 | Apr 28 2019

Roskoski R Jr indicated that Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors. These agents are effective against cell lines that are resistant to B-Raf and MEK1/2 inhibitor therapy. Although MK-8353 does not directly inhibit MEK1/2, it decreases the phosphorylation of ERK1/2 as well as the phosphorylation of RSK, an ERK1/2 substrate. The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway. [Read the Full Post]

Quantitative Interrogation of the Human Kinome Perturbed by Two BRAF Inhibitors

255 | Apr 27 2019

We confirmed that vemurafenib could compromise the ATP binding capacity of MAP2K5 in vitro and inhibit its kinase activity in cells. [Read the Full Post]

A possible mechanism for hepatotoxicity induced by BIRB-796, an orally active p38 mitogen-activated protein kinase inhibitor

304 | Apr 25 2019

Iwano S et al. indicated that a reactive intermediate of BIRB-796 was detected by the glutathione-trapping method using mouse and human liver microsomes. The production of this reactive metabolite in the liver may be one of the causes of BIRB-796's hepatotoxicity. [Read the Full Post]

In vitro anti-osteoclastogenic activity of p38 inhibitor doramapimod via inhibiting migration of pre-osteoclasts and NFATc1 activity

306 | Apr 17 2019

Moon SH et al. suggested anti-osteoclastogenic activity of doramapimod via inhibiting migration/fusion of pre-osteoclasts and NFATc1 activity. [Read the Full Post]

Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial

385 | Apr 03 2019

Planchard D et al. found that Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAFV600E-mutant NSCLC. [Read the Full Post]

Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia

296 | Feb 11 2019

Campbell CT et al. demonstrated TER models of the DOT1L inhibitor pinometostat and provided useful tools for investigating clinical resistance. [Read the Full Post]

Leukotriene B₄ Metabolism and p70S6 Kinase 1 Inhibitors: PF-4708671 but Not LY2584702 Inhibits CYP4F3A and the ω-Oxidation of Leukotriene B₄ In Vitro and In Cellulo

366 | Feb 10 2019

Archambault AS et al. showed that PF-4708671 inhibits CYP4F3A and prevents the ω-oxidation of LTB4 in cellulo, which might result in increased LTB4 levels in vivo. [Read the Full Post]

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

297 | Jan 26 2019

Diamond EL et al. highlighted the importance of comprehensive genomic analysis of these disorders. [Read the Full Post]

MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation

745 | Jan 21 2019

Zhao Y et al. may elucidate a possible mechanism explaining the ineffectiveness of MEK inhibitors in breast cancer treatment and improve our understanding of the role of MEK in cancer. [Read the Full Post]

Down-Regulation of AQP4 Expression via p38 MAPK Signaling in Temozolomide-Induced Glioma Cells Growth Inhibition and Invasion Impairment

585 | Jan 19 2019

Chen Y et al. identified that TMZ might have therapeutic potential for controlling proliferation, invasion of malignant glioma by inhibiting AQP4 expression through activation of p38 signal transduction pathway. [Read the Full Post]

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

358 | Nov 29 2018

Niessner H et al. presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma. [Read the Full Post]

DCLK1 is correlated with MET and ERK5 expression, and associated with prognosis in malignant pleural mesothelioma

362 | Nov 22 2018

Wang H et al. suggested that DCLK1 is regulated by MET/ERK5 signaling in human mesothelioma, and the MET/ERK5/DCLK1 signaling cascade could be further developed into a promising therapeutic target against mesothelioma. [Read the Full Post]

Oncogenic KRas-induced Increase in Fluid-phase Endocytosis is Dependent on N-WASP and is Required for the Formation of Pancreatic Preneoplastic Lesions

379 | Nov 17 2018

Lubeseder-Martellato C et al. defined a new role of FPE as a tumor initiating mechanism. [Read the Full Post]

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

378 | Nov 12 2018

Zhou H et al. provided a potential target for diagnosis and therapeutic treatment of breast cancer. [Read the Full Post]

Pro-survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

0 | Nov 06 2018

Chen Y et al. showed that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of cyclin-dependent kinase inhibitors in CLL in combination with other relevant targeted therapies. [Read the Full Post]

Reactivation of the p90RSK-CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2-M Arrest and Mediates Acquired Resistance to Ganetespib in KRAS-Mutant NSCLC

473 | Nov 02 2018

Chatterjee S et al. showed protective effects in OVX-induced OA partly through the TGF-β1 pathway. [Read the Full Post]

PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib]

825 | Oct 19 2018

Booth L et al. argued that additional clinical studies combining pemetrexed, sorafenib and sildenafil are warranted. [Read the Full Post]

The selective MEK1 inhibitor Selumetinib enhances the antitumor activity of everolimus against renal cell carcinoma in vitro and in vivo

381 | Oct 17 2018

Zou Y et al. provided a sound evidence that combination of everolimus and Selumetinib is a potential dual-targeted strategy for renal cell carcinoma. [Read the Full Post]

Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy

1976 | Aug 26 2018

Zhang P et al. suggested that the upregulation of PD-L1 promotes a resistance response in lung cancer cells that might be through activation of the phosphatidylinositol 3-kinase/protein kinase B pathway and suppression of tumor-infiltrating lymphocytes. The high expression of PD-L1 after NAC could be an indication of therapeutic resistance and poor prognosis in patients with non-small-cell lung cancer. [Read the Full Post]

Honokiol Induces Apoptosis, G1 Arrest, and Autophagy in KRAS Mutant Lung Cancer Cells

1064 | Aug 22 2018

Luo LX et al. indicated these results broaden our understanding of the mechanisms on honokiol effects in lung cancer, and reinforce the possibility of its potential anticancer benefit as a popular Chinese herbal medicine (CHM). [Read the Full Post]

Nesfatin-1 protects dopaminergic neurons against MPP+/MPTP-induced neurotoxicity through the C-Raf-ERK1/2-dependent anti-apoptotic pathway

0 | Jul 02 2018

Shen XL et al. suggested that C-Raf-ERK1/2, which is involved in an anti-apoptotic pathway, is responsible for the neuroprotective effects of nesfatin-1 in the context of MPTP-induced toxicity. These results imply that nesfatin-1 might have therapeutic potential for PD. [Read the Full Post]

miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways

516 | Jul 01 2018

Sun X et al. demonstrated that miR-7 could reverse the resistance to BRAF inhibitors in certain vemurafenib resistant melanoma cell lines. It could advance the field and provide the basis for further studies in BRAF inhibitor resistance in melanoma. [Read the Full Post]

Identification of approved and investigational drugs that inhibit hypoxia-inducible factor-1 signaling

960 | Jun 27 2018

Hsu CW et al. underline the importance of developing a battery of robust assay platforms and confirmation studies that focus on endogenous protein targets so that only relevant and reliable data will be taken into pre-clinical and clinical studies. [Read the Full Post]

Ionizing Radiation Induces Altered Neuronal Differentiation by mGluR1 through PI3K-STAT3 Signaling in C17.2 Mouse Neural Stem-Like Cells

479 | Jun 22 2018

Eom HS et al. suggested that the IR-induced altered neuronal differentiation may play a role in the brain dysfunction caused by IR. [Read the Full Post]

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

613 | Jun 22 2018

Jeric I et al. indicated the contribution of the cellular/tissue environment in determining the function of a protein, and underscores the importance of understanding the molecular context of a disease to inform therapy design. [Read the Full Post]

Registered report: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

523 | Jun 21 2018

Bhargava A et al. indicated that cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. [Read the Full Post]

AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo

2795 | Jun 20 2018

Xi Y et al. supported the progression of this molecule into future evaluation as a valuable anti-gastric cancer candidate. [Read the Full Post]

RAD51 inhibition in triple negative breast cancer cells is challenged by compensatory survival signaling and requires rational combination therapy

481 | Jun 13 2018

Wiegmans AP et al. highlight a potential compensatory mechanism via p38 that limits DNA targeted therapy. [Read the Full Post]

Registered report: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF

513 | Jun 11 2018

Bhargava A et al. indicated that Heidorn and colleagues report that paradoxical activation of the RAF-RAS-MEK-ERK pathway by BRAF inhibitors when applied to BRAF(WT) cells is a result of BRAF/CRAF heterodimer formation upon inactivation of BRAF kinase activity, and occurs only in the context of active RAS. [Read the Full Post]

Proliferation of the human urothelium is induced by atypical β1 -adrenoceptors

596 | Jun 05 2018

Winder M et al. showed that the urothelium expresses atypical β1-adrenoceptors that activate intracellular kinases inducing urothelial proliferation. [Read the Full Post]

Signaling effects of sodium hydrosulfide in healthy donor peripheral blood mononuclear cells

609 | Jun 04 2018

Sulen A et al. provided a description of a NaHS-induced signal transduction pathway in human primary immune cells that may have relevance for the role of sulfides in inflammation. [Read the Full Post]

Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events

511 | May 24 2018

Yang P et al. indicated that loss of SMC-Tgfbr1 triggers multiple deleterious pathways, including abnormal TGFBR2, ERK, and AngII/AT1R signals that disrupt aortic wall homeostasis to cause aortic aneurysm formation. [Read the Full Post]

Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells

567 | May 23 2018

Gonçalves-Ribeiro S et al. showed that STAT3 or P38 inhibition provides a promising strategy for overcoming microenvironment-mediated resistance. Conversely, pharmacologic AKT inhibition induces an antagonistic effect that relieves a cMET and STAT3-mediated compensatory feedback that might explain the failure of AKT inhibitors in the clinic so far. [Read the Full Post]

Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines

571 | May 23 2018

Fernández ML et al. showed the greatest anti-proliferative effects. This study serves as a basis for much needed future research on MEKi drug efficacy in LGSC. [Read the Full Post]

DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival

481 | May 22 2018

Wingert S et al. indicated that genotoxic stress-induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system. [Read the Full Post]

Increased translocation of antigens to endosomes and TLR4 mediated endosomal recruitment of TAP contribute to nicotine augmented cross-presentation

650 | May 09 2018

Wang YY et al. suggested that increased recruitment of TAP to Ag-containing vesicles contributes to the superior cross-presentation efficacy of α7 nAchR activated DCs. [Read the Full Post]

Anandamide Suppresses Proinflammatory T Cell Responses In Vitro through Type-1 Cannabinoid Receptor-Mediated mTOR Inhibition in Human Keratinocytes

608 | May 08 2018

Chiurchiù V et al. demonstrated that AEA suppresses highly pathogenic T cell subsets through CB1-mediated mammalian target of rapamycin inhibition in human keratinocytes. Thus, it can be speculated that the latter pathway might be beneficial to the physiological function of the skin, and can be targeted toward inflammation-related skin diseases. [Read the Full Post]

Connexin 32-mediated cell-cell communication is essential for hepatic differentiation from human embryonic stem cells

837 | Apr 22 2018

Qin J et al. suggested that Cx32 is essential for cell-cell interactions that facilitate driving hESCs through hepatic-lineage maturation. Regulators of both Cx32 and other members of its pathways maybe used as a promising approach on regulating hepatic lineage restriction of pluripotent stem cells and optimizing their functional maturation. [Read the Full Post]

Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth

766 | Mar 31 2018

Dewaele M et al. concluded that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target. [Read the Full Post]

Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma

0 | Mar 27 2018

Ezell SA et al. indicated that combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL. [Read the Full Post]

Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response

0 | Mar 27 2018

Luo Y et al. identified Tsc1 as a crucial signaling checkpoint in DCs essential for preserving T-cell homeostasis and response. [Read the Full Post]

Intestinal Microbiota-Derived GABA Mediates Interleukin-17 Expression during Enterotoxigenic Escherichia coli Infection

744 | Mar 26 2018

Ren W et al. highlight the importance of intestinal GABA signaling in intestinal IL-17 expression during intestinal infection and indicate the potential of intestinal microbiota-GABA signaling in IL-17-associated intestinal diseases. [Read the Full Post]

Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response

1351 | Feb 27 2018

Luo Y et al. identified Tsc1 as a crucial signaling checkpoint in DCs essential for preserving T-cell homeostasis and response. [Read the Full Post]

Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance

560 | Feb 23 2018

Shaffer SM et al. found that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general program in which expression is displayed in rare subpopulations of cells. [Read the Full Post]

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

773 | Feb 12 2018

He H et al. indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ. [Read the Full Post]

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

685 | Feb 06 2018

El Bezawy R et al. showed impressive inhibitory effects induced by miR-34a on DMPM cell proliferation, invasion, and growth in immunodeficient mice strongly suggest the potential clinical utility of a miR-34a-replacement therapy for the treatment of such a still incurable disease. On the other hand, we provide the first evidence of a potential cytoprotective/resistance mechanism that may arise towards miRNA-based therapies through the persistent activation of RTK downstream signaling. [Read the Full Post]

Pan-Raf co-operates with PI3K-dependent signalling and critically contributes to myeloma cell survival independently of mutated RAS

580 | Jan 30 2018

Müller E et al. indicated concomitant pan-Raf/PI3K inhibition was also effective in carfilzomib- and lenalidomide-resistant MM models underscoring that this attractive therapeutic anti-MM strategy is suitable for immediate clinical translation. [Read the Full Post]

ERK5 activation is essential for osteoclast differentiation

607 | Jan 29 2018

Amano S et al. showed that activation of the MEK5/ERK5 pathway with M-CSF is required for osteoclast differentiation, which may induce differentiation through the induction of c-Fos. [Read the Full Post]

Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells

623 | Jan 28 2018

Boutin A et al. concluded that TSH regulates expression of different bone markers via distinct signaling pathways. [Read the Full Post]

The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer

0 | Jan 24 2018

Beadnell TC et al. demonstrated that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition. [Read the Full Post]

Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer

670 | Jan 23 2018

Queralt B et al. showed that synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors. [Read the Full Post]

Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines

610 | Jan 23 2018

Fernández ML et al. showed the greatest anti-proliferative effects. This study serves as a basis for much needed future research on MEKi drug efficacy in LGSC. [Read the Full Post]

Vascular CXCR4 Expression Promotes Vessel Sprouting and Sensitivity to Sorafenib Treatment in Hepatocellular Carcinoma

999 | Dec 22 2017

Xu J et al. revealed that CXCR4 is a novel HCC vascular marker for vessel sprouting and could serve as a potential therapeutic target and a predictive factor for sorafenib treatment in patients with HCC. [Read the Full Post]

Effect of earthworm active protein on fibroblast proliferation and its mechanism

747 | Dec 09 2017

Song S et al. demonstrated that EAP is effective in promoting effects on proliferation and migration activity of NIH3T3 cell, and the proliferation activity of EAP on NIH3T3 cell may be achieved through the PI3K→Rac→PAK→MEK signaling pathway. [Read the Full Post]

Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma

1293 | Dec 08 2017

Combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL. [Read the Full Post]

Optogenetic clustering of CNK1 reveals mechanistic insights in RAF and AKT signalling controlling cell fate decisions

1145 | Dec 08 2017

Fischer A et al. found that CNK1 expression, CNK1 clustering and the thereto related differential signalling processes decide on proliferation and differentiation in a cell type- and cell stage-dependent manner by orchestrating AKT and RAF signalling. [Read the Full Post]

Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells

0 | Dec 01 2017

Zhou C et al. showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. JNK-dependent mPTP necrosis pathway could be key mechanism responsible for ICT's actions. [Read the Full Post]

An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases

742 | Nov 20 2017

Urisman A et al. obtained from these analyses reveal compensatory activation of TGF-β family receptors as a response to MAPK blockade. The gains achieved using this label-free PRM multiplexing strategy will benefit a wide array of biological applications. [Read the Full Post]

CQ synergistically sensitizes human colorectal cancer cells to SN-38/CPT-11 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk

1170 | Nov 18 2017

Chen P et al. showed that CQ could enhance CRC cells response to CPT-11 (a prodrug of SN-38) in xenograft models. Thus the combined treatment might represent an attractive therapeutic strategy for the treatment of CRC. [Read the Full Post]

NMR Characterization of Information Flow and Allosteric Communities in the MAP Kinase p38γ

1862 | Nov 16 2017

Aoto PC et al. demonstrated that the approach detects critical junctions in the network corresponding to biologically significant allosteric sites and pathways. [Read the Full Post]

Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells

1176 | Nov 11 2017

Zhou C et al. showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. [Read the Full Post]

Hepatocyte growth factor reduces sensitivity to the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib, in lung adenocarcinoma cells harboring wild-type EGFR

0 | Nov 02 2017

Yang H et al. suggested that HGF reduced the gefitinib sensitivity through MET and downstream PI3K and MAPK pathways. [Read the Full Post]

Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6

795 | Oct 29 2017

Carson WF 4th et al. indicated that CCL2 supports the classical activation of macrophages, with miR-9 mediated down-regulation of Dusp6 and enhanced ERK-mediated signal transduction possibly mediating this enhanced pro-inflammatory gene expression. [Read the Full Post]

SP600125 enhances the anti-apoptotic capacity and migration of bone marrow mesenchymal stem cells treated with tumor necrosis factor-α

1119 | Oct 11 2017

Wei B et al. suggested that SP600125 is of potential use in promoting the regeneration of bone and cartilage in OA and RA. [Read the Full Post]

Effects of bavachin and its regulation of melanin synthesis in A375 cells

0 | Oct 10 2017

Wang JH, et al. found that bavachin inhibited the synthesis of melanin on A375 cells by inhibiting the protein and mRNA expression of TYR, TRP-1, TRP-2, ERK1, ERK2 andJNK2. [Read the Full Post]

Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4

0 | Oct 08 2017

Zeng Q et al. provided critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4. [Read the Full Post]

MEK inhibitor CI-1040 induces apoptosis in acute myeloid leukemia cells in vitro

760 | Oct 07 2017

Wei CR et al. demonstrated that CI-1040 induce apoptosis of U-937 cells and might be a new therapeutic option for the treatment of AML. [Read the Full Post]

Effect of earthworm active protein on fibroblast proliferation and its mechanism

0 | Oct 01 2017

Song S et al. demonstrated that EAP is effective in promoting effects on proliferation and migration activity of NIH3T3 cell, and the proliferation activity of EAP on NIH3T3 cell may be achieved through the PI3K→Rac→PAK→MEK signaling pathway. [Read the Full Post]

Multiplexed Fluorescence Imaging of ERK and Akt Activities and Cell-cycle Progression

0 | Sep 18 2017

Maryu G et al. provided a useful tool for quantifying the dynamics among ERK and Akt activities and the cell cycle in a live cell, and for addressing the mechanisms underlying intrinsic resistance to molecularly targeted drugs. [Read the Full Post]

BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

0 | Sep 08 2017

Zhang ZX et al. indicated that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. [Read the Full Post]

TIMP-1 expression induced by IL-32 is mediated through activation of AP-1 signal pathway

0 | Aug 18 2017

Xu H, et al. believed that IL-32 might be involved in the pathogenesis of hepatic fibrosis by inducing TIMP-1 expression. [Read the Full Post]

Phosphorylation of the RNA-binding protein Dazl by MAPKAP kinase 2 regulates spermatogenesis

0 | Aug 18 2017

Williams PA et al. suggested that signaling by the p38-MK2 pathway is a negative regulator of spermatogenesis via phosphorylation of Dazl. [Read the Full Post]

Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein-Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

0 | Aug 12 2017

Jones RJ et al. concluded LTP may reactivate EBV-positive resting memory B cells thereby enhancing EBV lytic cycle and host immune suppression [Read the Full Post]

TGF-β1 promotes Staphylococcus aureus adhesion to and invasion into bovine mammary fibroblasts via the ERK pathway

1860 | Aug 07 2017

Zhao S et al. indicated that TGF-β1 could promote S. aureus adhesion to and invasion into BMFBs by increasing Collagen I and α-SMA expression and may provide a novel target for controlling bovine mastitis. [Read the Full Post]

Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis

814 | Jul 19 2017

Lu YX et al. suggest that nafamostat mesilate, a relatively non-toxic drug that targets NF-κB and Erk, may, in combination with oxaliplatin, represent a novel therapeutic strategy for CRC treatment. [Read the Full Post]

Analysis of Endogenous Protein Interactions of Polycomb Group of Proteins in Mouse Embryonic Stem Cells

0 | Jul 06 2017

Morey L et al. described several methods to study Polycomb architecture, and identification of novel interactors in both pluripotent and differentiating mouse embryonic stem cells. [Read the Full Post]

Inhibition of acquired-resistance hepatocellular carcinoma cell growth by combining sorafenib with phosphoinositide 3-kinase and rat sarcoma inhibitor

988 | Jul 06 2017

J Surg Res have showed that both inhibitors of PI3K/mTOR and RAS/ERK signaling are potentially effective antihepatocellular carcinoma drugs especially in treating sorafenib-resistant hepatocellular carcinoma. [Read the Full Post]

The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib

1011 | Jul 05 2017

Park KS et al. showed that intrinsic resistance to MEK inhibition occurred via high AKT expression by PI3K activation as a bypass pathway. The HSP90 inhibitor AUY922 suppressed PI3K-AKT-mTOR and RAF-MEK-ERK, and rendered cells sensitive to trametinib (GSK1120212). Synergy from the combination of the two drugs was observed in only sub-therapeutic concentrations of either drug. Dual inhibition of the HSP90 and MEK signaling pathways with sub-therapeutic doses may represent a potent therapeutic strategy to treat KRAS-mutant NSCLC with intrinsic resistance to MEK inhibition and to resolve the toxicity observed upon dual inhibition of AKT and MEK at therapeutic doses in clinical trials. [Read the Full Post]

Adiponectin promotes human jaw bone marrow mesenchymal stem cell chemotaxis via CXCL1 and CXCL8

2780 | Jul 02 2017

Pu Y et al. suggested that APN can promote h-JBMMSC chemotaxis by up-regulating CXCL1 and CXCL8. [Read the Full Post]

The mechanically activated p38/MMP-2 signaling pathway promotes bone marrow mesenchymal stem cell migration in rats

984 | Jul 02 2017

Yang Z et al. demonstrated that static strain can promote the migration ability of BMMSCs via p38/MMP-2 signaling. To the best of our knowledge, this study is the first report demonstrating that the p38/MMP-2 axis governs BMMSC migration under static mechanical strain. [Read the Full Post]

Cdk5 is required for the neuroprotective effect of transforming growth factor-β1 against cerebral ischemia-reperfusion

2720 | Jun 21 2017

Zhao W et al. concluded that Cdk5 contributes to the neuroprotective function of TGF- β1 via ERK1/2 signaling. [Read the Full Post]

Hypoxia-induced vasculogenic mimicry formation in human colorectal cancer cells: Involvement of HIF-1a, Claudin-4, and E-cadherin and Vimentin.

991 | Jun 20 2017

Li W et al. revealed a regulatory role for HIF-1α in VM and suggests that targeting either HIF-1α or EMT may be a valuable strategy for the elimination of CRC metastasis. [Read the Full Post]

Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, in KRAS-Mutant NSCLC Is Mediated via Reactivation of the ERK-p90RSK-mTOR Signaling Network

1844 | Jun 20 2017

Chatterjee S et al. offered a way forward for Hsp90 inhibitors through the rational design of Hsp90 inhibitor combinations that may prevent and/or overcome resistance to Hsp90 inhibitors, providing an effective therapeutic strategy for KRAS-mutant NSCLC. [Read the Full Post]

Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer

0 | Jun 19 2017

Pappalardo F et al. showed a computational model able to simulate the main biochemical and metabolic interactions in the PI3K/AKT and MAPK pathways potentially involved in melanoma development. [Read the Full Post]

Inhibition of acquired-resistance hepatocellular carcinoma cell growth by combining sorafenib with phosphoinositide 3-kinase and rat sarcoma inhibitor

909 | Jun 15 2017

Wu CH et al. found that both inhibitors of PI3K/mTOR and RAS/ERK signaling are potentially effective antihepatocellular carcinoma drugs especially in treating sorafenib-resistant hepatocellular carcinoma. [Read the Full Post]

Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro

968 | Jun 13 2017

Qu Z et al. found the important role of HCC cell-derived exosomes in the drug resistance of liver cancer cells and demonstrate the intrinsic interaction between exosomes and their targeted tumor cells. [Read the Full Post]

miRNA-106a directly targeting RARB associates with the expression of Na(+)/I(-) symporter in thyroid cancer by regulating MAPK signaling pathway

1047 | Jun 10 2017

Shen CT et al. provided new strategies for the diagnosis and treatment in radioiodine-refractory differentiated thyroid carcinoma. [Read the Full Post]

Interferon-Gamma and Fas Are Involved in Porphyromonas gingivalis-Induced Apoptosis of Human Extravillous Trophoblast-Derived HTR8/SVneo Cells via Extracellular Signal-Regulated Kinase 1/2 Pathway

1220 | May 30 2017

Ren H et al. demonstrated Pg induces IFN-γ secretion, Fas expression, and apoptosis in human extravillous trophoblast-derived HTR8/SVneo cells in an ERK1/2-dependent manner, and IFN-γ (explored by recombinant IFN-γ) and Fas are involved in Pg-induced apoptosis. [Read the Full Post]

Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells

0 | May 23 2017

Sponziello M et al. found that FN1 overexpression is an important determinant of thyroid cancer aggressiveness. [Read the Full Post]

Additive effects of low concentrations of estradiol-17β and progesterone on nitric oxide production by human vascular endothelial cells through shared signaling pathways

1125 | May 21 2017

Pang Y et al. suggested that low doses of E2 and P4 may also have some beneficial cardiovascular effects in vivo when administered as hormone replacement therapy (HRT) for post-menopausal women. [Read the Full Post]

Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway

0 | May 19 2017

Mao J et al. highlighted that the secretion of IL-1β and STAT3 activation induced by Arsenic trioxide can be mediated by elevation of P38/JNK MAPK in HAPI microglia cells and then induced the toxicity of neurons. [Read the Full Post]

Neuritin Mediates Activity-Dependent Axonal Branch Formation in Part via FGF Signaling.

3639 | May 07 2017

Shimada T et al suggested that neuritin and FGF cooperate in inducing mossy fiber sprouting through FGF signaling. Together, these results suggest that FGF and neuritin-mediated axonal branch induction are involved in the aggravation of epilepsy. [Read the Full Post]

MEK-ERK inhibition potentiates WAY-600-induced anti-cancer efficiency in preclinical hepatocellular carcinoma (HCC) models

1411 | May 03 2017

Wang K et al demonstrated the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK inhibitors. [Read the Full Post]

Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer

0 | Apr 26 2017

Francica P et al. suggested that FOXM1 has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. [Read the Full Post]

Urotensin II-induced insulin resistance is mediated by NADPH oxidase-derived reactive oxygen species in HepG2 cells

1313 | Apr 22 2017

Li YY et al. found that UII induces insulin resistance, and this can be reversed by JNK inhibitor SP600125 and antioxidant/NADPH oxidase inhibitor apocynin targeting the insulin signaling pathway in HepG2 cells. [Read the Full Post]

P53 Is Involved in a Three-Dimensional Architecture-Mediated Decrease in Chemosensitivity in Colon Cancer

0 | Apr 20 2017

He J et al suggested that p53 is involved in a 3D architecture-mediated decrease in chemosensitivity to platinum in colon cancer. Mitogen-activated protein kinases (JNK1/2 and p38) do not play a dominant role in the mechanism. [Read the Full Post]

Inhibition of Phospho-S6 Kinase, a Protein Involved in the Compensatory Adaptive Response, Increases the Efficacy of Paclitaxel in Reducing the Viability of Matrix-Attached Ovarian Cancer Cells.

3107 | Apr 17 2017

Choi JI et al found that addition of BX795 or CCT128930 to inhibit pS6 (S240/S244) or pS6 (S235/S236) restricted the compensatory adaptive response to paclitaxel in HeyA8 and SKOV3 cells. These inhibitors increased the efficacy of paclitaxel in reducing cancer cell viability. [Read the Full Post]

Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

0 | Apr 10 2017

Fu M et al indicated that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. [Read the Full Post]

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

6636 | Apr 09 2017

Collectively, Wu C et al revealed, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth. [Read the Full Post]

Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation

2691 | Apr 03 2017

Huang A et al revealed a metabolic signature of sorafenib-resistant cells and suggests that glycolytic inhibition may override such resistance and warrant further clinical investigation. [Read the Full Post]

Small-Molecule Induction of Canine Embryonic Stem Cells Toward Naïve Pluripotency

918 | Mar 25 2017

Tobias IC et al. suggested that 2iL culture conditions promote the conversion of cESCs toward an epigenetically distinct pluripotent state resembling naïve PSCs. [Read the Full Post]

MITF depletion elevates expression levels of ERBB3 receptor and its cognate ligand NRG1-beta in melanoma

1105 | Mar 24 2017

Alver TN et al. suggested that MITF may play a role in the development of acquired drug resistance through hyper-activation of the PI3K pathway. [Read the Full Post]

Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells

1419 | Feb 18 2017

Zhou C, et al.'s results showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. JNK-dependent mPTP necrosis pathway could be key mechanism responsible for ICT's actions. [Read the Full Post]

MEK Inhibition Sensitizes Precursor B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells to Dexamethasone through Modulation of mTOR Activity and Stimulation of Autophagy

0 | Feb 16 2017

Polak A et al. demonstrated that modulation of MEK/ERK pathway is an attractive therapeutic strategy overcoming GC resistance in B-ALL patients. [Read the Full Post]

Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells

1778 | Jan 08 2017

Zhou C, et al.‘s results showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. JNK-dependent mPTP necrosis pathway could be key mechanism responsible for ICT's actions. [Read the Full Post]

BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

0 | Dec 24 2016

Zhang ZX et al. indicated that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. [Read the Full Post]

Canonical FGFs Prevent Osteogenic Lineage Commitment and Differentiation of Human Bone Marrow Stromal Cells Via ERK1/2 Signaling

1125 | Dec 19 2016

Simann M et al. presented new findings indicating that canonical FGFR-ERK1/2 signaling entrapped hBMSCs in a pre-committed state and arrested further maturation of committed precursors. [Read the Full Post]

BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

1207 | Dec 18 2016

Kemper K et al.'s results illustrated the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients. [Read the Full Post]

TIMP-1 expression induced by IL-32 is mediated through activation of AP-1 signal pathway

1718 | Dec 07 2016

Xu H et al. believe that IL-32 might be involved in the pathogenesis of hepatic fibrosis by inducing TIMP-1 expression. [Read the Full Post]

Phosphorylation of the RNA-binding protein Dazl by MAPKAP kinase 2 regulates spermatogenesis

1499 | Dec 06 2016

The results of Williams PA et al. illuminate a novel role for MK2 in spermatogenesis, expand the repertoire of RNA-binding proteins phosphorylated by this kinase, and suggest that signaling by the p38-MK2 pathway is a negative regulator of spermatogenesis via phosphorylation of Dazl. [Read the Full Post]

BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

1364 | Dec 03 2016

Zhang ZX et al. indicated that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. [Read the Full Post]

Multiplexed Fluorescence Imaging of ERK and Akt Activities and Cell-cycle Progression

1340 | Nov 26 2016

Maryu G et al.'s study provides a useful tool for quantifying the dynamics among ERK and Akt activities and the cell cycle in a live cell, and for addressing the mechanisms underlying intrinsic resistance to molecularly targeted drugs. [Read the Full Post]

MEK inhibitor CI-1040 induces apoptosis in acute myeloid leukemia cells in vitro

1166 | Nov 21 2016

Wei CR et al. demonstrated that CI-1040 induce apoptosis of U-937 cells and might be a new therapeutic option for the treatment of AML. [Read the Full Post]

Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4

1306 | Nov 20 2016

Zeng Q et al. provided critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4. [Read the Full Post]

Effects of bavachin and its regulation of melanin synthesis in A375 cells

1368 | Nov 18 2016

Bavachin inhibited the synthesis of melanin on A375 cells by inhibiting the protein and mRNA expression of TYR, TRP-1, TRP-2, ERK1, ERK2 andJNK2. [Read the Full Post]

The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer

1344 | Nov 18 2016

Beadnell TC et al. demonstrated that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition. [Read the Full Post]

MEK Inhibition Sensitizes Precursor B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells to Dexamethasone through Modulation of mTOR Activity and Stimulation of Autophagy.

1403 | Nov 07 2016

Polak A, et al found that the data demonstrate that modulation of MEK/ERK pathway is an attractive therapeutic strategy overcoming GC resistance in B-ALL patients. [Read the Full Post]

Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer

1372 | Oct 31 2016

FOXM1, a negative regulator of senescence, has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. [Read the Full Post]

EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines

1142 | Oct 26 2016

[Read the Full Post]

Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells

1320 | Oct 20 2016

Sponziello M et al. indicated that FN1 overexpression is an important determinant of thyroid cancer aggressiveness. [Read the Full Post]

Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway

1858 | Oct 17 2016

Mao J et al. highlighted that the secretion of IL-1β and STAT3 activation induced by Arsenic trioxide can be mediated by elevation of P38/JNK MAPK in HAPI microglia cells and then induced the toxicity of neurons. [Read the Full Post]

P53 Is Involved in a Three-Dimensional Architecture-Mediated Decrease in Chemosensitivity in Colon Cancer

1317 | Sep 21 2016

He J et al. suggested that p53 is involved in a 3D architecture-mediated decrease in chemosensitivity to platinum in colon cancer. [Read the Full Post]

Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

1537 | Sep 13 2016

Fu M, et al. found that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. [Read the Full Post]

Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation

0 | Sep 08 2016

Huang A, et al. revealed a metabolic signature of sorafenib-resistant cells and suggests that glycolytic inhibition may override such resistance and warrant further clinical investigation. [Read the Full Post]

ERK induces degradation of tumor suppressor FBW7 in pancreatic cancer

6904 | Mar 18 2015

Ji et al. demonstrated a correlation between low expression of FBW7 and ERK activation in pancreatic cancer. [Read the Full Post]

αB-crystallin induces by matrix detachment via ERK is critical in inhibition of anoikis

7299 | Mar 05 2015

Malin et al. identified an matrix detachment-induced antiapoptotic molecular chaperone, αB-crystallin, confers anoikis resistance. [Read the Full Post]

The roles of physiological and synthetic IAP antagonism on c-IAP1/2 degradation

3146 | Mar 04 2015

Kocab et al. took a system approach to extensively compare the transcriptional programs triggered by CD30, which can degrade c-IAPs to SM-164, a synthetic IAP antagonist induces c-IAP degradation. [Read the Full Post]

Alternative functions of K-RAS in endocrine tumors

2497 | Jan 29 2015

Chamberlian et al. found K-RAS suppresses the growth in pancreatic endocrine cells, in contrast to its promoting effect on other cancer cells. [Read the Full Post]

MAPK cascade promotes early axonal degeneration in response to injury

5640 | Jan 21 2015

By using traumatic injury as a model, Yang et al. demonstrated a critical role of mitogen-activated protein kinase (MAPK) cascade in early axonal degeneration in response to injury. [Read the Full Post]

The important role of Cav1 in inducing peritoneal membrane epithelial-mesenchymal transition and fibrosis

2536 | Jan 13 2015

Strippoli et al. found Caveolin-1 (Cav1) acts as a critical factor in the increasing epithelial-mesenchymal transition (EMT), thickness, and fibrosis of peritoneum during peritoneal dialysis. [Read the Full Post]

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

11441 | Jan 07 2015

Winter et al. identified the underlying mechanism of the emerging JAK2 inhibitor therapy resistance in MPNs patients, and found the RAS and pathways mediated by AKT and ERK contribute to the resistance. [Read the Full Post]

The important role of immune microenvironment in resistance to MAPK pathway-targeted therapy

2124 | Jan 04 2015

Smith et al. demonstrated that the factors within immune microenvironment can promote the resistance to mitogen-activated protein kinase (MAPK) pathway-targeted therapy. [Read the Full Post]

Two states of BRAFV600 mutant melanoma that related to MAPK inhibition resistance

6799 | Dec 31 2014

Konieczkowski et al. revealed the mechanism of MAPK inhibition on BRAFV600 mutant melanomas. [Read the Full Post]

Novel approach of genetic perturbation

2228 | Dec 18 2014

Konermann et al. built a CRISPR-Cas9 complex for the regulation of effective transcriptional activation at target genomic loci. [Read the Full Post]

The early resistance to BARF(V600)-mutant melanoma is triggered by reactivation of MAPK pathway

2957 | Dec 12 2014

In regards to mechanism of emerging drug resistance, Long et al. demonstrated MAPK pathway was reactivated in early stage of resistance to combination therapy. [Read the Full Post]

ERK/Cdk5 axis regulates diabetes-related PPARγ phosphorylation

7429 | Nov 21 2014

Recently, Banks et al. discovered that ERK/Cdk5 axis is involved in regulation PPARγ activities, and the inhibition of ERK and MEK leads to the improvement of insulin resistance. [Read the Full Post]

The mechanism of drug resistance in BRAF (V600E) mutant melanoma

9114 | Nov 19 2014

Sun et al. demonstrated the resistance of BRAF (V600E) is reversible and adaptive. The process involves several transduction factors, such as EGFR, PDGFRB, TGF-β, and SOX10. [Read the Full Post]

PD0325901 is a potent MEK inhibitor that suppresses phosphorylation of ERK1

2246 | Mar 03 2014

PD0325901 (PD325901) is selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. [Read the Full Post]

RAF265 is a potent selective inhibitor of C Raf

2452 | Feb 21 2014

RAF265 shows 71% to 72% TVI% (tumor volume inhibition percentage) in HCT116 xenografts at 12 mg/kg. [Read the Full Post]

PLX4032 was able to reduce numbers of cancer cells

0 | Jan 21 2014

Vemurafenib is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM. [Read the Full Post]

SP600125 is a reversible ATP competitive inhibitor

2990 | Jan 14 2014

SP600125 is originally characterized as a selective ATP-competitive inhibitor of c-Jun N-terminal kinase JNK. [Read the Full Post]

VX 702 is A p38 MAP kinase inhibitor

2486 | Jan 09 2014

VX-702 is a highly selective inhibitor of p38α MAPK, 14-fold higher potency against the p38α versus p38β. [Read the Full Post]

AZD6244 is not competitive with ATP and inactivates the ERK1

2165 | Jan 07 2014

AZD6244 has little effects on the p38, c-Jun-NH2-kinase, phosphatidylinositol 3-kinase, and MEK5/ERK5 pathways. [Read the Full Post]

AZD6244 is a drug being investigated for the treatment of various types of cancer

0 | Dec 03 2013

AZD6244 is not competitive with ATP and inactivates the ERK1/2 phosphorylation with IC50 concentrations below 40 nM. [Read the Full Post]

PLX4032 was able to reduce numbers of cancer cells

2453 | Nov 20 2013

Vemurafenib (PLX4032, RG7204) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM. [Read the Full Post]

PD184352 is an inhibitor of mitogen activated protein kinase

2252 | Nov 19 2013

CI-1040 (PD 184352) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM, 100-fold more selective for MEK1/2 than MEK5. Phase 2. [Read the Full Post]

AZD6244 is a drug being investigated for the treatment of various types of cancer

2234 | Nov 15 2013

AZD6244 is not competitive with ATP and inactivates the ERK1/2 phosphorylation with IC50 concentrations below 40 nM. [Read the Full Post]

PD 0325901 is a selective and ATP non competitive MEK inhibitor

2313 | Nov 15 2013

PD0325901 (PD325901) is selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 1/2. [Read the Full Post]

RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors

2770 | Nov 06 2013

RAF265 inhibits C-Raf, wild type B-Raf and mutant (V600E) B-Raf. RAF265 effectively block phosphorylation of Raf's downstream substrates MEK and ERK in cells and also kill melanoma and colorectal cancer cell lines harboring B-Raf mutations independent of PTEN mutation status. [Read the Full Post]

PD0325901 is selective and non ATP competitive MEK inhibitor

2205 | Oct 17 2013

PF0325901 shows higher permeability than CI-1040, another MEK inhibitor. PD0325901 should be able to achieve higher systemic exposures than CI-1040. [Read the Full Post]

SB203580 is a selective inhibitor of p38 mitogen activated protein kinase

3205 | Oct 16 2013

SB203580 inhibits the IL-2-induced proliferation of primary human T cells, murine CT6 T cells, or BAF F7 B cells with an IC50 of 3–5 μm. [Read the Full Post]

U0126 is a highly selective inhibitor of both MEK1 and MEK2

0 | Oct 11 2013

U0126-EtOH functionally antagonizes AP- 1 transcriptional activity and blocks the production of a variety of cytokines and metalloproteinases involved in the inflammatory response. [Read the Full Post]

Sorafenib is used to treat advanced renal cell carcinoma

2498 | Sep 22 2013

Sorafenib tosylate inhibits both wild-type and V599E mutant B-Raf activity with IC50 of 22 nM and 38 nM, respectively. [Read the Full Post]

PLX4032 is a highly selective inhibitor of BRAF kinase activity

2620 | Sep 05 2013

PLX4032 is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM. [Read the Full Post]

U0126 is a highly selective inhibitor of both MEK1 and MEK2

2435 | Aug 02 2013

U0126-EtOH functionally antagonizes AP- 1 transcriptional activity and blocks the production of a variety of cytokines and metalloproteinases involved in the inflammatory response. [Read the Full Post]

Trametinib had good results for V600E mutated metastatic melanoma

2548 | Jul 25 2013

GSK1120212 inhibits the phosphorylation of MBP regardless of the isotype of Raf and MEK, with IC50 ranging from 0.92 nM to 3.4 nM. GSK1120212 demonstrates no inhibition of the kinase activities of c-Raf, B-Raf, ERK1 and ERK2. [Read the Full Post]

Selumetinib is a drug being investigated for the treatment of various types of cancer

2135 | May 08 2013

AZD6244 also inhibits the growth of primary HCC cells through inhibition of ERK1/2 and p90RSK phosphorylation, accompanied with elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. [Read the Full Post]

SP600125 is supplied as a lyophilized powder

3152 | Apr 26 2013

SP600125 is originally characterized as a selective ATP-competitive inhibitor of c-Jun N-terminal kinase JNK. In Jurkat T cells, SP600125 inhibits the phosphorylation of c-Jun with IC50 of 5 μM to 10 μM. [Read the Full Post]

PD98059 is a potent and selective inhibitor of MAP kinase

2205 | Apr 10 2013

PD98059 inhibits either basal MEK1 or a partially activated MEK produced by mutation of serine at residues 218 and 222 to glutamate (MEK-2E) with IC50 of 2 μM. PD98059 does not inhibit the MAPK homologues JNK and P38. PD98059 is highly selective against MEK, as it does not inhibit a number of other kinase activities including Raf kinase, cAMP-dependent kinase, protein kinase C, v-Src, epidermal growth factor (EGF) receptor kinase, insulin receptor kinase, PDGF receptor kinase, and phosphatidylinositol 3-kinase. [Read the Full Post]

PD98059 is a non ATP competitive MEK inhibitor with IC50

2243 | Mar 27 2013

PD98059 inhibits either basal MEK1 or a partially activated MEK produced by mutation of serine at residues 218 and 222 to glutamate (MEK-2E) with IC50 of 2 μM. PD98059 does not inhibit the MAPK homologues JNK and P38. [Read the Full Post]

MEK inhibition in BRAF mutated melanoma

2110 | Dec 24 2012

Systemic efforts to decipher the molecular mechanisms MEK inhibition of these actions led to the isolation of the mTOR protein and the identification of two multimolecular complexes that are formed bymTOR [Read the Full Post]

MEK PATHWAY INHIBITION FOR CANCER THERAPY

2573 | Aug 13 2012

SIGNALLING OF MEK PATHWAY: Various types of cells exist on the surface of the cells helping the cells to coordinate with the environment and the other cells. The growth factor receptors are such receptors which after getting triggered by the ligands usually play a very vital role in the process of cell signaling hence stimulate different pathways that are necessary for the cell survival and growth. One such example is MEK kinase cascade that plays an important role in pro-survival signaling. The inhibition of MEK kinase pathway is one of the attractive strategies when there is a need to inhibit un-necessary proliferation of cells in case of cancer. It has been studied that MEK signaling pathway gets hyperactivated in the cancer cells, so scientists devised a good therapeutic tool against cancer by designing different inhibitors of MEK pathway. 20 years ago, the structural properties of MEK molecule were described [1], which make the approach of scientists much easier for specific MAP2k2 inhibitor. [Read the Full Post]

MEK INHIBITOR AGAINST UNCONTROLLED GROWTH OF CELLS

2868 | Aug 07 2012

MEK – RECEPTORS: Growth factor receptor is found on the surface of cells and upon stimulation a protein is encoded in the nucleus which is vital for cell signaling. A type of kinases is called MEK that is important for the pro-survival signaling. An easy approach to hinder or control the pro-survival signaling is the inhibition of MEK which can be done by designing MEK kinase inhibitor. The most suitable example of is of cancer cells which is characterized by uncontrolled cell proliferation and in these cells MEK signaling pathway is found as hyperactivated, hence the introduction of MEK pathway inhibitors is the appropriate therapy. About 20 years back the structure of MEK was elucidated, due to this researcher are aided well for the development of specific MEK inhibitors. [Read the Full Post]

B-RAF INHIBITOR FOR TUMORS

2390 | Apr 23 2012

V600E MUTATION AND B-RAF PATHWAY: B-Raf, a proto-oncogene is a serine/threonine kinase protein playing a major role in different signalling cascades which regulates cell growth and this B-Raf proto-oncogene in humans is encoded by B-RAF gene. B-Raf is found to be affecting the processes of cell division and cell differentiation by playing a regulatory role in ERK and MAPK signaling cascades. Any sort of acquired mutation in this gene leads to abnormalities in related signaling cascades as a result uncontrolled cell division and growth which leads to cancer eventually while an inherited mutation was found to be linked with cardiofaciocutaneous syndrome which is a birth defect. For this reason the use of BRaf inhibitor for the inhibition of B-Raf pathways is found to be a valuable and attractive approach. More than thirty mutations found to be clustered in activation and flanking regions of B-Raf gene and they were analyzed as well. It was observed that substitution of Valine with Glutamic acid at codon number 600 is very abundant, clinically relevant and most famous one and this mutation (V6000E) is targeted the most as compared to B-Raf selective inhibitor. [Read the Full Post]

PLX4032 – THE B-RAF ANTAGONIST

2279 | Mar 19 2012

Introduction: The Effect of B-Raf mutation Cellular pathways are sequences of chemical reactions that take place in the cell membrane, cytosole and the nucleus to initiate, control or regulate processes necessary for normal function. A protein called RAS is anchored in the cell membrane and upon activation with GTP can bind to another protein called RAF [1]. With transfer of a phosphate group from GTP the RAF protein becomes detached and activated. Moving through the cytosole start the signal of RAF is passed on to MEK and then to ERK by means of phosphorylation. Eventually the signal reaches the cell nucleus and growth processes are started depending on the original signal. Therefore, it can be seen that Raf and MEK are two proteins whose major function is to carry a signal from membrane to nucleus to ensure cell survival. Any form of deviation from the normal situation in regards to these two proteins would cause significant problems. With regards to Raf three isoforms have been isolated and characterized known as A,B or C-Raf. [Read the Full Post]

PD98059 – THE MOST COMMON MEK INHIBITOR

3132 | Mar 20 2012

Introduction: The Mitogen-Activated Protein Kinase Protein kinases are responsible for much of the activation, control and regulation of the cell cycle processes, such activities as cell division, cell migration, gene transcription and apoptosis. Typical a kinase cascade exists where a trans membrane kinase is activated by an extra cellular factor such as growth factors, mitogens, stress factors and cytokines. The top level of the MAP kinases are referred to as MAP kinase kinase kinases and examples are the Raf series of proteins, MLK3, TAK, MEKK1, 2,3 &4 which trigger signaling cascades down to the next level of proteins usually located either bonded to the inner membrane or in the cell cytosole. Second level kinases examples are MEK1/2 or 5, MKK3/4 or 6/7. The last level MAP kinases are usually located in the mitochondria / nucleus membranes or in either the mitochondria / nucleus themselves. The extensive nature of the MAPK pathways means that they are significantly involved in the normal and abnormal growth patterns of the mammalian system. [Read the Full Post]

AZD6244 – INHIBITNG MEK

2541 | Mar 18 2012

The Inhibition of MEK MEK (also known as MAPK) is part of a pathway the links the extracellular signals to the nucleus and consists of RAS, a tyrosine kinase protein attached inter-cellularly to the membrane. RAF, a cytosolic protein which shifts to the membrane under the influence of activated RAS, MEK a cytosolic protein that is activated by the action of a phosphorylated RAF, it has a highly specific activity for ERK ( the last member of the pathway, located in the nucleus and active in gene transcription, cellular growth and cell cycle regulation. The interesting fact is the Raf and Erk both can have one of multiple targets but MEK is dedicated to Erk only. This high degree of specificity means that MEK is a prime target for inhibition and the subsequent interference in this pathway. The RAS – ERK pathway has been investigated thoroughly in both normal and tumor tissues where it has been found that in numerous tumor tissues this pathway is over expressed. [Read the Full Post]

PD0325901 – SUCCESS OF A MEK INHIBITOR

3396 | Mar 19 2012

Introduction: MEK inhibition In numerous tumors investigates for kinase activity one of the key pathways to stand out is the RAS / RAF pathway. With mutations of both RAS (KRAS) and RAF (BRafV600E) demonstrating significant resistance in chemotherapeutic action for EGFR, RAS and RAF inhibitors, a target further down the signaling pathway was thought to be a possible side step to this resistance. EGFR is a transmembrane protein which passes a signal (via phosphorylation) to an internal membrane bound protein (GRBS and SOS). This signal is passed down stream via RAS and RAF to a nexus point, MEK. This protein is the target of several pathway crossovers and while MEK itself has not been shown to be mutated; it is recipient of signals from several proteins that are. Signaling via MEK can lead to several different functions in the cell include cell growth, proliferation and migration. [Read the Full Post]

MEK INHIBITOR AGAINST SUSTAINED GROWTH OF CELLS

2374 | Mar 19 2012

Introduction: The RAS-Raf-MEK-MAPK pathway One of the pathways researched in relation to cancerous properties is that of the RAS-Raf –MEK-MAPK phosphorylation signaling cascade. This pathway has been linked with the regulation of gene transcription via the nucleus receptor MAPK. The pathway is initiated via transmembrane receptor proteins such as EDGR, VEGFR, PDGFR or IGFR which receives an extracellular signal via ligand binding which is translated into the phosphorylation of the membrane bound protein RAS via the exchange of GDP for GTP in the complex receptor protein SOS and GRB2. RAS is the description of a family of proteins with a signature binding domain they are located in the intracellular side to the cell membrane. [Read the Full Post]

B-RAF INHIBITOR AGAINST CANCERS

3281 | Mar 13 2012

The mechanism of the RAS-Raf pathway In the normal situation cells will live and die on a regular basis, maintaining healthy tissue and organs. To control this process there are several signaling pathway which either stimulate the cell to proliferate or induce the normal sequence of events for cell death (Apoptosis). The pathway which controls cell proliferation, cell differentiation and cell growth is the RAS/Raf/MEK/Erk pathway Growth is initiated by the activation of RAS, which is located in the plasma membrane, by activation of its tyrosine kinase receptor by extracellular growth factors. The RAS protein receptors are on the external face of the cell while signal is conducted inside the cell. Growth factors activate the external RAS protein so the internal root of the RAS protein complexes with Raf proteins activating them. The raf proteins then actively phosphorylates the MEK protein which in turn phosphorylates the Erl protein and cell division /proliferation beginnings. The role of Raf is therefore to carry the signal from the activated RAS and to MEK protein in the cytosole/nuclease to initiate proliferation activity, the signal also acts as a cell survival mechanism. [Read the Full Post]

JNK, a potential therapeutic target for the treatment of nephrotoxicity

3530 | Nov 14 2011

Nephrotoxicity is a poisonous effect of some substances, including toxic chemicals and medication, on the kidneys, and cyclosporine (CsA) nephrotoxicity is one kind of nephrotoxicity. It is reported that the epithelial to mesenchymal transition(EMT) is an important mechanism contributing to the pathogenesis of cyclosporine (CsA) nephrotoxicity by promoting the generation of myofibroblasts. Some studies suggested that he endoplasmic reticulum (ER) stress as a potential mechanism may participate in the modulation of tubular cell plasticity in CsA-induced EPCs[1]. However, the precise mechanisms have not been known. [Read the Full Post]

Raf kinases, the excellent molecular targets for anticancer therapy

3349 | Oct 31 2011

Raf kinases are a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes. Raf kinases mainly contain three mammalian RAF proteins (A, B and CRAF) and participate in the RAS-RAF-MEK-ERK signal pathways. Of which, B-Raf is the family member most easily activated by Ras, and the kinase activity of B-Raf is higher than that of C-Raf and, likely, A-Raf. Thus, the frequent mutational activation of BRAF is often observed in human tumors, but not CRAF or ARAF. [Read the Full Post]

Sorafenib, a potential therapy for Chronic lymphocytic leukemia patients

2677 | Oct 13 2011

Chronic lymphocytic leukemia (CLL) is a common leukemia which causes a slow increase in white blood cells called B lymphocytes, or B cells. This cancer mostly affects adults, around age 70, and leads to approximately 5000 deaths annually. The frontline therapy for CLL mainly use several chemotherapy drugs alone or in combination, such as Fludarabine, chlorambucil, cyclophosphamide, and rituximab. Besides, bone marrow or stem cell transplantation may be used in younger patients with advanced or high-risk CLL. [Read the Full Post]

S6K and PDK1 modulate neuronal size specification

6129 | Sep 22 2011

Synapse is located in the nervous system and a structure that passes an electrical or chemical signalfrom a neuron to another cell. The presynaptic terminal is a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles. Active zones is a region that synaptic vesicles are docked at the presynaptic plasma membrane. [Read the Full Post]

p38 MAPK inhibitor, FR167653, a potent therapy against PTHrP-induced osteoclastogenesis and bone resorption-related diseases

3313 | Sep 07 2011

Study on mechanism indecates that PTHrP stimulates osteoclastogenesis by increasing receptor activator of NF-kB ligand (RANKL) expression. p38 MAPK is required for osteoclast differentiation. This implies the existence of relationship between p38 MAPK and PTHrP in osteoclastogenesis. [Read the Full Post]

Dietrich, J., V. Gokhale, et al. (2010). "Application of a novel [3+2] cycloaddition reaction to prepare substituted imidazoles and their use in the design of potent DFG-out allosteric B-Raf inhibitors." Bioorg Med Chem 18(1): 292-304.

2756 | Jul 15 2011

An article about drug discovery of b-raf inhibitor design and molecular modeling. [Read the Full Post]

Munoz, L. and A. J. Ammit (2010). "Targeting p38 MAPK pathway for the treatment of Alzheimer

2751 | Jul 14 2011

This is an introduction of the relationship between p38 MAPK and Alzheimer's disease because p38 MAPK plays an important role in Alzheimer's disease. It also list the p38 MAPK inhibitors Alzheimer's disease patients could benefit from. [Read the Full Post]

Wong, K. K. (2009). "Recent developments in anti-cancer agents targeting the Ras/Raf/ MEK/ERK pathway." Recent Pat Anticancer Drug Discov 4(1): 28-35.

2493 | Jul 12 2011

Give an introduction of inhibitors targeting the Ras/Raf/ MEK/ERK pathway. This article summaries the current and future development of anti-cancer drugs or inhibitors of Ras/Raf/ MEK/ERK pathway and the difference between those drugs or inhibitors. [Read the Full Post]

Roux, P. P. and J. Blenis (2004). "ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions." Microbiol Mol Biol Rev 68(2): 320-344.

3073 | Apr 9 2011

Give a introduction of physiological functions of ERK and P38 MAPK. [Read the Full Post]

Hagemann, C. and J. L. Blank (2001). "The ups and downs of MEK kinase interactions." Cell Signal 13(12): 863-875.

2469 | Mar 18 2011

A review focus on MEK. This review summarises the upstream and downstream of MEK. It give a detail introduction of the targets which interact with MEK. [Read the Full Post]

Davis, R. J. (2000). "Signal transduction by the JNK group of MAP kinases." Cell 103(2): 239-252.

4189 | Mar 9 2011

This is an classic review which introduce role of the JNK Signaling Pathway in MAPKKK pathway, cell survival and apoptosis. [Read the Full Post]