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Proteases

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

4 | 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]

Notch Signaling Pathway Is a Potential Therapeutic Target for Extracranial Vascular Malformations

0 | Jun 22 2020

Reema B Davis et al. provided further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations. [Read the Full Post]

A Systematic Review of the Studies That Evaluate the Performance of the DAPT Score

23 | Jun 21 2020

Chun Shing Kwok et al. showd that the DAPT score had modest predictive value for ischemic and bleeding outcomes.A prospective randomized controlled trial was needed to evaluate the clinical benefits of utilising the DAPT score in guiding continued DAPT therapy beyond 1 year. [Read the Full Post]

Targeting the Ubiquitin-Proteasome Pathway to Overcome Anti-Cancer Drug Resistance

16 | Jun 20 2020

Silpa Narayanan et al. discussed various PIs and their underlying mechanisms in surmounting anti-tumor drug resistance when used in combination with conventional chemotherapeutic agents. [Read the Full Post]

DAPT Score and the Impact of Ticagrelor Monotherapy During the Second Year After PCI

27 | Jun 18 2020

Ply Chichareon et al. found that the DAPT score can stratify ischemic but not bleeding risk in a contemporary PCI population during the second year. [Read the Full Post]

Prediction of Therapeutic Outcome and Survival in a Transgenic Mouse Model of Pancreatic Ductal Adenocarcinoma Treated With Dendritic Cell Vaccination or CDK Inhibitor Using MRI Texture: A Feasibility Study

11 | Jun 17 2020

Aydin Eresen et al. demonstrated that MRI texture features had great potential to generate diagnosis and prognosis models for monitoring early treatment response following dinaciclib drug or DC vaccine treatment and also predicting histopathological tumor markers and long-term clinical outcomes. [Read the Full Post]

Cooperativity Between Orthosteric Inhibitors and Allosteric Inhibitor 8-Anilino-1-Naphthalene Sulfonic Acid (ANS) in Cyclin-Dependent Kinase 2

15 | Jun 16 2020

Erik B Faber et al. detailed the positive cooperativity between ANS and orthosteric Cdk2 inhibitors dinaciclib and roscovitine, which increased the affinity of ANS toward Cdk2 5-fold to 10-fold, and the relatively noncooperative effects of ATP. [Read the Full Post]

Pyruvate Anaplerosis Is a Mechanism of Resistance to Pharmacological Glutaminase Inhibition in Triple-Receptor Negative Breast Cancer

15 | Jun 02 2020

Dean C Singleton et al. highlighted the potential influence that both circulating and tumour-derived pyruvate could have on glutaminase inhibitor efficacy. Furthermore, they highlighted the benefits of 3D spheroid cultures to model the features of the tumour microenvironment and improved the in vitro investigation of cancer metabolism-targeted therapeutics. [Read the Full Post]

MG-132 Attenuates Cardiac Deterioration of Viral Myocarditis via AMPK Pathway

24 | May 28 2020

Xin-Min Zhang et al. found that MG-132 modulated apoptosis and inflammation, improved hemodynamics, and inhibited the structural remodeling of ventricles in a myocarditis mouse model via regulation of the AMPK signal pathway. [Read the Full Post]

Inhibition of Apoptosis by Caspase Inhibitor Z-VAD-FMK Improves Cryotolerance of in Vitro Derived Bovine Embryos

0 | May 26 2020

Maria Elena Pero et al. found that the addition of 20 μM Z-VAD-FMK during vitrification/warming and post-warming culture partially inhibited cryopreservation-induced apoptosis by reducing the level of active caspase 3, suggesting a potential used as an additive to ameliorate the efficiency of embryo cryopreservation in cattle, critical for a further diffusion of IVEP technology in the field. [Read the Full Post]

Caspase-3 Inhibitor Z-DEVD-FMK Enhances Retinal Ganglion Cell Survival and Vision Restoration After Rabbit Traumatic Optic Nerve Injury

50 | Apr 28 2020

Yuanyuan Liu et al. showed the caspase-3 inhibitor Z-DEVD-FMK is neuroprotective by inhibiting RGCs apoptosis when injected 30 min after optic nerve damage and significantly promotes restoration of vision. A controlled clinical trial is now needed to evaluate the efficacy and safety of Z-DEVD-FMK in humans. [Read the Full Post]

Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations

0 | Apr 11 2020

Davis RB et al. provided further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations. [Read the Full Post]

Impact of high on-treatment platelet reactivity after angioplasty in patients with peripheral arterial disease

106 | Apr 10 2020

Busch L et al. suggested that MALE might be associated with dual HTPR. [Read the Full Post]

Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis

0 | Apr 06 2020

Mancarella S et al. provided new knowledge on Notch signaling in iCCA, and support the inhibition of the Notch cascade as a promising strategy for the treatment of this disease. [Read the Full Post]

Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells

97 | Mar 26 2020

Augello G et al. indicated their results offer hope for a new therapeutic opportunity in the treatment of HCC patients. [Read the Full Post]

An Ilomastat-CD Eye Drop Formulation to Treat Ocular Scarring

56 | Mar 06 2020

Mohamed-Ahmed AHA et al. showed that Ilomastat-CD has the potential to be formulated as an eye drop for use as an antifibrotic, which may have implications for the prevention of scarring in many settings, for example glaucoma filtration surgery. [Read the Full Post]

Crenigacestat, a Selective NOTCH1 Inhibitor, Reduces Intrahepatic Cholangiocarcinoma Progression by Blocking VEGFA/DLL4/MMP13 Axis

200 | Feb 23 2020

Serena Mancarella et al. developed and validated a new iCCA PDX model to test in vivo the activity of LY3039478, demonstrating its inhibitory role in Notch-dependent angiogenesis. Thus, the present data provide new knowledge on Notch signaling in iCCA, and support the inhibition of the Notch cascade as a promising strategy for the treatment of this disease. [Read the Full Post]

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition

85 | Feb 14 2020

Hong AL et al. identified a synthetic lethal relationship between SMARCB1-deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors. [Read the Full Post]

Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001

119 | Jan 28 2020

Shaw AT et al. showed the clinically meaningful benefit and safety of crizotinib in this molecular subgroup. [Read the Full Post]

Daratumumab prevents programmed death ligand-1 expression on antigen-presenting cells in de novo multiple myeloma

97 | Jan 28 2020

Stocker N et al. suggested new mechanisms of action of Dara through depletion of pDC and prevention of PD-L1 upregulation expression on APC. Our finding provides new evidences for development of therapeutic strategies targeting both CD38 and PD-L1/PD-1 pathway in patients with MM. [Read the Full Post]

Isoflavones Isolated from the Seeds of Millettia ferruginea Induced Apoptotic Cell Death in Human Ovarian Cancer Cells

87 | Jan 18 2020

Wang YY et al. suggested that DMI induced apoptotic cell death through the intrinsic pathway via ROS production, while ferrugone stimulated the extrinsic pathway in human ovarian cancer cells. [Read the Full Post]

Suppression of human T cell proliferation by the caspase inhibitors, z-VAD-FMK and z-IETD-FMK is independent of their caspase inhibition properties

0 | Jan 12 2020

Lawrence CP and Chow SC demonstrated that both z-VAD-FMK and z-IETD-FMK are immunosuppressive in vitro and inhibit T cell proliferation without blocking the processing of caspase-8 and caspase-3. [Read the Full Post]

Diacylglycerol kinase δ destabilizes serotonin transporter protein through the ubiquitin-proteasome system

118 | Jan 04 2020

Lu Q et al. provide novel insights into serotonergic system regulation and the pathophysiology/therapeutics of serotonin-/SERT-related diseases such as obsessive-compulsive disorder, depression, autism and schizophrenia. [Read the Full Post]

Hypoxia-Induced Cleavage Of Soluble ephrinA1 From Cancer Cells Is Mediated By MMP-2 And Associates With Angiogenesis In Oral Squamous Cell Carcinoma

82 | Dec 04 2019

Ma TT et al suggested a possible novel mechanism that ephrinA1 secretion is mediated by HIF-1α/MMP-2 signaling cascade which may play pivotal roles in OSCC neovascularization in a paracrine manner. [Read the Full Post]

Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment

191 | Dec 02 2019

Pisklakova A et al. indicated that targeting Notch may be considered as a new strategy to be tested for MM therapy. [Read the Full Post]

An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancer

156 | Nov 07 2019

Wang H et al. developed a genotype-based strategy that identifies CK2 as a promising co-target in KRAS(G12C) mutant NSCLC by using available pharmacogenomics gene expression datasets. This approach is applicable to other oncogene driven cancers. [Read the Full Post]

The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway

0 | Nov 06 2019

Do Carmo H et al. indicated the caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection. [Read the Full Post]

Exogenous mesenchymal stem cells affect the function of endogenous lung stem cells (club cells) in phosgene-induced lung injury

0 | Oct 21 2019

Ye K et al. showed that MSCs reduced the secretion of club cells. And MSCs enhanced the proliferation of club cells partly via activating the Notch signaling pathway, which promoted lung injury repair. [Read the Full Post]

The anti-caspase inhibitor Q-VD-OPH prevents AIDS disease progression in SIV-infected rhesus macaques

183 | Oct 20 2019

Laforge M et al. demonstrated that Q-VD-OPH injection in SIV-infected RMs may represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS. [Read the Full Post]

The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis

193 | Oct 15 2019

Barreyro FJ et al. demonstrated that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy in NASH. [Read the Full Post]

Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas

173 | Sep 25 2019

Holkova B et al. showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response. [Read the Full Post]

Proteasome inhibitor PS-341 limits macrophage necroptosis by promoting cIAPs-mediated inhibition of RIP1 and RIP3 activation

166 | Aug 25 2019

Zhang Y et al. identified a new role of PS-341 in the cell death of BMDMs and provided a novel insight into the atherosclerotic inflammation caused by proteasome-mediated macrophage necroptosis. [Read the Full Post]

Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations

314 | Aug 18 2019

Davis RB et al. showed that two gamma secretase inhibitors (GSIs), DAPT (GSI-IX) and RO4929097, cause dose-dependent inhibition of Notch target gene expression (Hey1) and rate of migration of monolayer cultures of lymphatic endothelial cells (hLECs) and blood endothelial cells (HUVEC). GSIs also inhibit HUVEC network formation. hLECs are more sensitive to GSIs compared to HUVEC. GSIs have been found to be safe in clinical trials in patients with Alzheimer's disease or cancer. Our results provide further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations. [Read the Full Post]

Clinical relevance of ticagrelor monotherapy following 1-month dual antiplatelet therapy after bifurcation percutaneous coronary intervention: Insight from GLOBAL LEADERS trial

264 | Aug 16 2019

Kogame N et al. found that after PCI for bifurcation lesions using 1-month of DAPT followed by ticagrelor monotherapy for 23 months did not demonstrate explicit benefit regarding all-cause death or new Q-wave MI as in the overall trial. [Read the Full Post]

Use of Antiplatelet Therapy/DAPT for Post-PCI Patients Undergoing Noncardiac Surgery

275 | Aug 14 2019

Banerjee S et al. present3 commonly encountered clinical scenarios that lead into an evidence-based discussion of practical strategies for managing perioperative antiplatelet therapy in patients following percutaneous coronary intervention. [Read the Full Post]

Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer

112 | Jul 29 2019

Gross MI et al. provided a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors. [Read the Full Post]

Phenotypic Drug Screening for Dysferlinopathy Using Patient-Derived Induced Pluripotent Stem Cells

202 | Jul 24 2019

Kokubu Y et al. suggested that increasing the amount of misfolded dysferlin using small molecules could represent an effective future clinical treatment for dysferlinopathy. Stem Cells Translational Medicine2019. [Read the Full Post]

Inhibition of apoptosis by caspase inhibitor Z-VAD-FMK improves cryotolerance of in vitro derived bovine embryos

0 | Jul 22 2019

Pero ME et al. indicated the addition of 20 μM Z-VAD-FMK during vitrification/warming and post-warming culture partially inhibits cryopreservation-induced apoptosis by reducing the level of active caspase 3, suggesting a potential use as an additive to ameliorate the efficiency of embryo cryopreservation in cattle, critical for a further diffusion of IVEP technology in the field. Further studies are though needed to evaluate the effect of Z-VAD-FMK on post-transfer embryo development before considering a commercial application. [Read the Full Post]

Exogenous mesenchymal stem cells affect the function of endogenous lung stem cells (club cells) in phosgene-induced lung injury

275 | Jul 05 2019

Ye K et al. showed that MSCs reduced the secretion of club cells. And MSCs enhanced the proliferation of club cells partly via activating the Notch signaling pathway, which promoted lung injury repair. [Read the Full Post]

MMP14-Containing Exosomes Cleave VEGFR1 and Promote VEGFA-Induced Migration and Proliferation of Vascular Endothelial Cells

132 | Jun 16 2019

Han KY et al. showed that MMP14-containing exosomes may be involved in the regulation of corneal neovascularization through degradation of VEGFR1 and VEGFA-induced endothelial cell proliferation and migration. [Read the Full Post]

Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis

215 | Jun 10 2019

Tian J et al. concluded that combination of emricasan with ponatinib could synergistically reduce I/R injury in rat brain through simultaneous prevention of apoptosis and necroptosis. Our findings might lay a basis on extension of the clinical indications for emricasan and ponatinib in treating ischemic stroke. [Read the Full Post]

Inhibition of apoptosis by caspase inhibitor Z-VAD-FMK improves cryotolerance of in vitro derived bovine embryos

275 | May 17 2019

Pero ME et al. found that the addition of 20 μM Z-VAD-FMK during vitrification/warming and post-warming culture partially inhibits cryopreservation-induced apoptosis by reducing the level of active caspase 3, suggesting a potential use as an additive to ameliorate the efficiency of embryo cryopreservation in cattle, critical for a further diffusion of IVEP technology in the field. [Read the Full Post]

Molecular detection of Hsp90 inhibitor suppressing PCV2 replication in host cells

276 | May 13 2019

Liu J et al. highlighted the importance of cellular proteins during PCV2 infection and the possibility of targeting cellular chaperones for developing new anti-rotaviral strategies. [Read the Full Post]

Suppression of human T cell proliferation by the caspase inhibitors, z-VAD-FMK and z-IETD-FMK is independent of their caspase inhibition properties

343 | May 04 2019

Lawrence CP et al. demonstrated that both z-VAD-FMK and z-IETD-FMK are immunosuppressive in vitro and inhibit T cell proliferation without blocking the processing of caspase-8 and caspase-3. [Read the Full Post]

The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway

329 | Apr 22 2019

Do Carmo H et al. indicated the caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection. [Read the Full Post]

Memantine and Q-VD-OPh Treatments in Experimental Spinal Cord Injury: Combined Inhibition of Necrosis and Apoptosis

303 | Apr 05 2019

Aydoseli A et al showed that combined use of memantine and Q-VD-OPh provides better histological and clinical results. The combined inhibition of the two major pathways, necrosis and apoptosis, needs to be further assessed with in-vivo or in-vitro studies. [Read the Full Post]

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

360 | Mar 17 2019

Moreau P et al. showed the addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.). [Read the Full Post]

MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA

361 | Mar 17 2019

Wei X et al. indicated that NOXA knockdown by short hairpin RNA significantly attenuated the cytotoxicity of ABT-263 and MLN2238 co-administration. In conclusion, MLN2238 and ABT-263 synergistically triggered apoptosis in CRPC cells by upregulating NOXA and activating Bax, indicating a promising therapeutic strategy for the treatment of CRPC. [Read the Full Post]

Inhibition of the NOTCH pathway using γ-secretase inhibitor RO4929097 has limited antitumor activity in established glial tumors

1485 | Feb 05 2019

Dantas-Barbosa C et al. indicated that RO4929097-mediated effects were independent of NOTCH1 mutation status or expression levels, but associated with low IL-6 levels. In established glial tumor models, NOTCH inhibition had limited effects as a single agent, but enhanced efficacy when combined with DNA-interfering agents. These preclinical data need to be considered for further clinical development of NOTCH inhibitors in glial tumors. [Read the Full Post]

Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells

229 | Feb 03 2019

Thompson RM et al. suggested that the acquisition of PI resistance involves adaptations in cellular bioenergetics, supporting the combination of CB-839 with Crflz for the treatment of refractory MM. [Read the Full Post]

Dipeptidyl Peptidase-4 Induces Aortic Valve Calcification by Inhibiting Insulin-Like Growth Factor-1 Signaling in Valvular Interstitial Cells

255 | Jan 16 2019

Choi B et al. suggested that DPP-4 could serve as a potential therapeutic target to inhibit calcific aortic valve disease progression. [Read the Full Post]

Dabigatran reduces thrombin-induced platelet aggregation and activation in a dose-dependent manner

0 | Dec 25 2018

Vinholt PJ et al. indicated that dabigatran exclusively inhibits thrombin-induced platelet activation and aggregation with a dose-dependent response. Platelet stimulation with other agonists was not affected by dabigatran. [Read the Full Post]

Methods for 20S Immunoproteasome and 20S Constitutive Proteasome Determination Based on SPRI Biosensors

435 | Dec 06 2018

Anna S et al. indicated 20Si and 20Sc were determined in blood plasma samples from healthy donors and patients with acute leukemia. In the case of these patients 20Si was the major component, and its level was more than one order of magnitude higher than in the healthy donors. [Read the Full Post]

Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction

408 | Dec 02 2018

Wang L et al. suggested that compound 10 exhibits moderate inhibitory effect on Hsp90-Cdc37 and could be regard as a first evidence of a non-natural compound targeting Hsp90-Cdc37 PPI. [Read the Full Post]

Inhibition of glioblastoma cell proliferation, migration and invasion by the proteasome antagonist carfilzomib

0 | Nov 08 2018

Areeb Z, et al. indicated carfilzomib represents a novel, yet FDA-approved agent for the treatment of glioblastoma multiforme. [Read the Full Post]

Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons

416 | Oct 10 2018

Laidlaw SM et al. found TNF to have antiviral effects independently of, as well as in combination with, IFNs. TNF inhibits HCV infection despite increased HCV envelope glycoprotein-mediated infection of liver cells. These findings contradict those from other studies, which have reported that TNF blocks signal transduction in response to IFNs. The destructive inflammatory effects of TNF must be considered along with its antiviral effects. [Read the Full Post]

PTC725, an NS4B-Targeting Compound, Inhibits a Hepatitis C Virus Genotype 3 Replicon, as Predicted by Genome Sequence Analysis and Determined Experimentally

0 | Oct 09 2018

Graci JD et al. identified previously unreported amino acid substitutions selected by PTC725 treatment which further demonstrate that these compounds target the NS4B first transmembrane region. [Read the Full Post]

Identification of ACTG2 functions as a promoter gene in hepatocellular carcinoma cells migration and tumor metastasis

768 | Sep 11 2018

Wu Y et al. revealed a critical role of ACTG2 in HCC tumor metastasis, and renders it a novel target for the treatment of HCC. [Read the Full Post]

Fascin Is Critical for the Maintenance of Breast Cancer Stem Cell Pool Predominantly via the Activation of the Notch Self-Renewal Pathway

861 | Sep 11 2018

Barnawi R et al. demonstrated fascin as a critical regulator of breast CSC pool at least partially via activation of the Notch self-renewal signaling pathway and modification of the expression embryonic transcriptional factors. Targeting fascin may halt CSCs and thus presents a novel therapeutic approach for effective treatment of breast cancer. [Read the Full Post]

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces edema due to BBB disruption induced by MMP-9 activation in rat hippocampus

527 | Aug 16 2018

Pérez-Hernández M et al. provided evidence enough to conclude that MDMA induces edema of short duration due to BBB disruption mediated by MMP-9 activation. [Read the Full Post]

Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation

0 | Aug 16 2018

Tao YF et al. may provided new insights into the molecular mechanism of PLK1 in regulating autophagy. [Read the Full Post]

Hepatitis C Virus NS4B Can Suppress STING Accumulation To Evade Innate Immune Responses

692 | Aug 13 2018

Yi G et al. showed that 2a/JFH1 NS4B has an additional mechanism to evade STING signaling through suppressing STING accumulation. [Read the Full Post]

A profiling study of a newly developed HCVcc strain PR63cc's sensitivity to direct-acting antivirals

738 | Aug 12 2018

Tao W et al. showed that PR63cc was more resistant than JFH1 to the asunaprevir/daclatasvir combination treatment. In summary, our study systemically analyzed the DAA sensitivity of a new HCVcc strain and identified critical RAVs. These results are not only important for monitoring the emergence of drug-resistant mutations of current DAA therapies, but also valuable for developing next-generation DAAs. [Read the Full Post]

BMS-708163 and Nilotinib restore synaptic dysfunction in human embryonic stem cell-derived Alzheimer's disease models

1078 | Aug 07 2018

Nishioka H et al. suggested that the AD models we developed are promising materials for the discovery of AD drugs that target the expression of pre-synaptic proteins and synaptic function. [Read the Full Post]

Combined treatment of carfilzomib and z-VAD-fmk inhibits skeletal proteolysis and apoptosis and ameliorates cancer cachexia

611 | Aug 06 2018

Wang Q et al. found that Combined treatment with CFZ and z-VAD-fmk early in the development of cachexia was associated with signs of less proteolysis and apoptosis and less severe cachexia in a mouse model of cancer-induced cachexia. [Read the Full Post]

Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1

877 | Jul 29 2018

Wang Y et al. unraveled a novel molecular pathway driven by interactions between PrP and Notch1 in the progression of PDAC, supporting a critical tumor-promoting role of Notch1 in PrP-expressing PDAC tumors. [Read the Full Post]

Notch and Hedgehog in the thymus/parathyroid common primordium: Crosstalk in organ formation

899 | Jul 27 2018

Figueiredo M et al. offered novel evidence on the role of Notch signalling in T/PT common primordium development, in an Hh-dependent manner. [Read the Full Post]

Thyroid Hormone-Induced Activation of Notch Signaling is Required for Adult Intestinal Stem Cell Development During Xenopus Laevis Metamorphosis

892 | Jul 27 2018

Hasebe T et al. provided evidence for evolutionarily conserved role of Notch signaling in intestinal cell fate determination but more importantly reveal, for the first time, an important role of Notch pathway in the formation of adult intestinal stem cells during vertebrate development. Stem Cells 2017;35:1028-1039. [Read the Full Post]

Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function

1058 | Jul 25 2018

Wang W et al. suggested that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients. [Read the Full Post]

HIV-1 gp120 Glycoprotein Interacting with Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Down-Regulates Tight Junction Proteins to Disrupt the Blood Retinal Barrier and Increase Its Permeability

410 | Jul 09 2018

Qian YW et al. elucidated a novel mechanism by which HIV, type 1 invades ocular tissues and provides additional insights into the translocation or invasion process of ocular complication-associated pathogens. [Read the Full Post]

A simple and cost-saving phenotypic drug susceptibility testing of HIV-1

976 | Jul 05 2018

Weng Y et al. provided a useful tool for interpreting meaningful genotypic mutations and guiding tailored antiviral treatment of HIV/AIDS in clinical practice. [Read the Full Post]

Dissecting the molecular mechanisms that impair stress granule formation in aging cells

680 | Jul 04 2018

Moujaber O et al. demonstrated that the loss of CReP correlated with the aging-related hyperphosphorylation of eIF2α. Together, we have identified significant changes in the stress response of aging cells and provide mechanistic insights. Based on our work, we propose that the decline in SG formation can provide a new biomarker to evaluate cellular aging. [Read the Full Post]

Activation of Chymotrypsin-Like Activity of the Proteasome during Ischemia Induces Myocardial Dysfunction and Death

877 | Jun 12 2018

Sanchez G et al. suggested that selective inhibition of chymotrypsin-like activity of the proteasome during ischemia preserves key proteins for cardiomyocyte function and exerts a positive impact on cardiac performance after reperfusion. [Read the Full Post]

ADAMTS13 and 15 are not regulated by the full length and N-terminal domain forms of TIMP-1, -2, -3 and -4

516 | Jun 04 2018

Guo C et al. indicated that TIMPs are not the regulators of these two ADAMTS proteinases. [Read the Full Post]

Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-κB/GSDMD signal in mice adipose tissue

2036 | May 16 2018

Liu Z et al. revealed a novel function of melatonin on adipocyte pyroptosis, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory response. [Read the Full Post]

Myosin IIA-related Actomyosin Contractility Mediates Oxidative Stress-induced Neuronal Apoptosis

687 | May 16 2018

Wang Y et al. unraveled the biochemical and mechanistic mechanisms during oxidative stress-induced neuronal apoptosis and may be applicable for the development of therapies for CNS diseases. [Read the Full Post]

HMGB1-mediated autophagy decreases sensitivity to oxymatrine in SW982 human synovial sarcoma cells

758 | May 13 2018

Cai Y et al. showed that combining OMT with an inhibitor of autophagy or HMGB1 may make OMT more effective in the treatment of human synovial sarcoma. [Read the Full Post]

Investigating proteasome inhibitors as potential adjunct therapies for experimental cerebral malaria

701 | May 11 2018

Howland SW et al. reported here that bortezomib, which has been associated with neurological adverse events, accelerated death in ECM-infected mice. [Read the Full Post]

COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR

1570 | Apr 14 2018

Lu R et al. demonstrated that genetic inhibition of the isopeptidase activity of COPS5 is sufficient to re-sensitize the resistant breast cancer cells to tamoxifen-treatment, offering a potential therapeutic approach for endocrine-resistant breast cancer patients. [Read the Full Post]

X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response.

718 | Mar 16 2018

Zhao Z et al. found that the HSP90 inhibitory action and the potent antitumor activity, with the anti-HSR action, promise X66 a novel HSP90-targeted agent, which merits further research and development. [Read the Full Post]

Strain- and host species-specific inflammasome activation, IL-1β release, and cell death in macrophages infected with uropathogenic Escherichia coli

2126 | Feb 26 2018

Schaale K et al. indicated in mouse macrophages, CFT073-triggered inflammasome responses are completely NLRP3-dependent, and largely α-hemolysin-dependent. In contrast, UPEC activates an NLRP3-independent cell death pathway and an α-hemolysin-independent IL-1β secretion pathway in human macrophages. This has important implications for understanding UTI in [Read the Full Post]

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

0 | Feb 23 2018

Han T et al. proposed that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs [Read the Full Post]

Dabigatran reduces thrombin-induced platelet aggregation and activation in a dose-dependent manner

619 | Feb 18 2018

Vinholt PJ et al. found dabigatran exclusively inhibits thrombin-induced platelet activation and aggregation with a dose-dependent response. [Read the Full Post]

Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis

1032 | Jan 12 2018

Gong Z et al. offered a mechanistic basis to ameliorate cholestatic liver fibrosis by targeting inflammasome activation. [Read the Full Post]

Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells

1228 | Jan 05 2018

Zeng D et al. suggested that EZH2 inactivation by GSK126 is effective in killing MM cells and CSCs as a single agent or in combination with bortezomib. Clinical trial of GSK126 in patients with MM may be warranted. [Read the Full Post]

Identification of mouse cathepsin K structural elements that regulate the potency of odanacatib

678 | Jan 05 2018

Law S et al. determined and compared the structures of inhibitor-free mouse CatK (mCatK), hCatK and ODN bound to hCatK. [Read the Full Post]

PTC725, an NS4B-Targeting Compound, Inhibits a Hepatitis C Virus Genotype 3 Replicon, as Predicted by Genome Sequence Analysis and Determined Experimentally.

1010 | Dec 29 2017

Graci JD et al. identified previously unreported amino acid substitutions selected by PTC725 treatment which further demonstrate that these compounds target the NS4B first transmembrane region. [Read the Full Post]

Matrine induces Akt/mTOR signalling inhibition-mediated autophagy and apoptosis in acute myeloid leukaemia cells

935 | Dec 20 2017

Wu J et al. indicated that matrine exerts antitumour effect through apoptosis and autophagy, and the latter one might be a potential therapeutic strategy for AML. [Read the Full Post]

Leucovorin Enhances the Anti-cancer Effect of Bortezomib in Colorectal Cancer Cells.

1022 | Dec 16 2017

Wang S et al. found that the anti-cancer effect of bortezomib and present this novel combinatorial treatment against colorectal cancer. [Read the Full Post]

E platinum, a newly synthesized platinum compound, induces apoptosis through ROS-triggered ER stress in gastric carcinoma cells

1173 | Dec 09 2017

Wang X et al. indicated that E Platinum may be a potential and effective treatment for gastric cancer in clinical. [Read the Full Post]

Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes But Not Normal Lymphocytes

1164 | Nov 22 2017

Zhelev Z et al. suggested that melatonin is a promising supplementary component in chemotherapy which allows the therapeutic doses of anticancer drugs to be reduced, minimizing their side-effects. [Read the Full Post]

Inhibition of the Pentose-phosphate Pathway Selectively Sensitizes Leukemia Lymphocytes to Chemotherapeutics by ROS-independent Mechanism

1118 | Nov 21 2017

Zhelev Z et al. suggested that 6-ANA could be used as a supplementary component in anticancer chemotherapy, and would allows therapeutic doses of anticancer drugs to be reduced, thereby minimizing their side-effects. [Read the Full Post]

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

0 | Nov 18 2017

Han T et al. proposed that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides). [Read the Full Post]

Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment

1785 | Oct 24 2017

Katsushima K et al. showed that highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population. [Read the Full Post]

Blockage of glutaminolysis enhances the sensitivity of ovarian cancer cells to PI3K/mTOR inhibition involvement of STAT3 signaling

681 | Sep 25 2017

Guo L et al. showed that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy to overcome resistance to PI3K/Akt/mTOR inhibition. [Read the Full Post]

Role of BmDredd during Apoptosis of Silk Gland in Silkworm, Bombyx mori

1189 | Sep 04 2017

Chen RT et al. suggested that BmDredd plays a critical role in SG apoptosis. [Read the Full Post]

The Role of the Active Oxygen Produced from Gp91phox NADPH Oxidase on the Newborn Weight of Mouse Pups

1275 | Sep 03 2017

Keiichi Hiramoto et al. indicated that gp91phox NADPH oxidase produces ROS during graviditas. The ROS activate NLRP3, and NLRP3 leads to the production of caspase-1, which subsequently increases IL-1, thereby finally inducing IGF-1. Because the newborn weight is determined by IGF-1, gp91phox appears to be important for promoting fetal growth during graviditas. [Read the Full Post]

Assessment of the chemotherapeutic potential of a new camptothecin derivative, ZBH-1205

0 | Aug 11 2017

Wu D, et al. found that ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials. [Read the Full Post]

THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors

1589 | Aug 09 2017

Cayrol F et al. indicated the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients. [Read the Full Post]

Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members

1261 | Aug 08 2017

Sonntag T et al. suggested that the regulation of cellular targets by AMPK family members is more extensive than previously appreciated. [Read the Full Post]

Essential role of Notch4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer

1893 | Jul 25 2017

Bui QT et al. concluded Notch4 could be a potential target to prevent metastasis in TAM-resistant breast cancer. [Read the Full Post]

Endosulfan inhibits proliferation through the Notch signaling pathway in human umbilical vein endothelial cells

1802 | Jul 25 2017

Wei J et al. demonstrated that endosulfan inhibited proliferation through the Notch signaling pathway as a result of oxidative stress. In addition, endosulfan can damage the cytoskeleton and block mitosis, which may add another layer of toxic effects on endothelial cells. [Read the Full Post]

NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling.

1454 | Jun 08 2017

Wang Z et al. proposed that NEDD4L negatively regulates PIK3CA protein levels via ubiquitination and is required for the maintenance of PI3K-AKT signaling pathway. [Read the Full Post]

Nek2A/SuFu feedback loop regulates Gli-mediated Hedgehog signaling pathway

0 | Jun 07 2017

Zhou F et al. uncovered one of the mechanisms by which Nek2A acts as a modulator of the Hh signaling pathway in the context of a novel negative-feedback loop, which may offer new insights into Gli-mediated Hh signaling regulation in development and human diseases. [Read the Full Post]

Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate

0 | Jun 06 2017

Hoffman M et al. found that a cell-based model reflects the effects on thrombin generation of clinically relevant levels of FVIIa and PCC in the presence of dabigatran. [Read the Full Post]

Receptor for Activated C Kinase 1 (RACK1) Promotes Dishevelled Protein Degradation via Autophagy and Antagonizes Wnt Signaling.

1422 | May 02 2017

Cheng M et al reported that receptor for activated C kinase 1 (RACK1) negatively regulates Dishevelled stability and Wnt signaling. RACK1 interacts with Dvl proteins and promotes their lysosomal degradation, and this effect is enhanced by autophagy induction. RACK1 also interacts with LC3 and enhances the association of LC3 with Dvl2, thereby leading to degradation of Dvl proteins through autophagy. These findings reveal a novel regulatory function of RACK1 in Wnt signaling by modulating Dvl stability. [Read the Full Post]

Tetrachlorobenzoquinone induces Nrf2 activation via rapid Bach1 nuclear export/ubiquitination and JNK-P62 signaling

1299 | Apr 21 2017

Su C et al. found that TCBQ-induced activation of Nrf2 involves c-Jun N-terminal kinase (JNK)-P62 signaling. [Read the Full Post]

Reversal of Dabigatran Effects in Models of Thrombin Generation and Hemostasis by Factor VIIa and Prothrombin Complex Concentrate

0 | Mar 25 2017

Hoffman M et al suggested that a cell-based model reflects the effects on thrombin generation of clinically relevant levels of FVIIa and PCC in the presence of dabigatran. Enhancing the rate of thrombin generation and peak thrombin level appear to correlate best with hemostasis in vivo. The ineffectiveness of FVIIa at supratherapeutic dabigatran levels may explain conflicting reports of its efficacy in dabigatran reversal. [Read the Full Post]

Assessment of the chemotherapeutic potential of a new camptothecin derivative, ZBH-1205

0 | Mar 04 2017

Wu D et al. found that ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials. [Read the Full Post]

X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response

1459 | Feb 25 2017

The HSP90 inhibitory action and the potent antitumor activity, with the anti-HSR action, promise X66 a novel HSP90-targeted agent, which merits further research and development. [Read the Full Post]

Solitary inhibition of the breast cancer resistance protein (BCRP) efflux transporter results in a clinically significant drug-drug interaction with rosuvastatin by causing up to a two-fold increase in statin exposure

2077 | Feb 25 2017

Elsby R, et al.'s result shows that solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant statin dose adjustment in clinical practice [Read the Full Post]

Targeting Wnt pathway in mantle cell lymphoma-initiating cells

0 | Feb 20 2017

Mathur R, et al.‘s’ results suggest that Wnt signaling is critical for the maintenance and survival of MCL-ICs, and effective MCL therapy should aim to eliminate MCL-ICs through Wnt signaling inhibitors. [Read the Full Post]

AKT and 14-3-3 Regulate Notch4 Nuclear Localization

2784 | Feb 06 2017

Ramakrishnan G, et al.'s findings provide a novel mechanism for Notch4-ICD regulation, suggesting a negative regulatory role for the PI3K-AKT pathway in Notch4 nuclear signaling. [Read the Full Post]

Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate

2165 | Jan 30 2017

The ineffectiveness of FVIIa at supratherapeutic dabigatran levels may explain conflicting reports of its efficacy in dabigatran reversal. [Read the Full Post]

Understanding the molecular mechanism of host-based statin resistance in hepatitis C virus replicon containing cells

1823 | Jan 28 2017

Delang L et al. demonstrated that statin resistance in HCV replicon containing hepatoma cells is conferred by changes in the cellular environment. [Read the Full Post]

Assessment of the chemotherapeutic potential of a new camptothecin derivative, ZBH-1205

0 | Jan 21 2017

Wu D et al. found that ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials. [Read the Full Post]

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

1084 | Jan 13 2017

Elsby R et al. found that solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant statin dose adjustment in clinical practice. [Read the Full Post]

Targeting Wnt pathway in mantle cell lymphoma-initiating cells

3790 | Jan 10 2017

Mathur R, et al.'s results suggest that Wnt signaling is critical for the maintenance and survival of MCL-ICs, and effective MCL therapy should aim to eliminate MCL-ICs through Wnt signaling inhibitors. [Read the Full Post]

Bifunctional alkylating agent-mediated MGMT-DNA cross-linking and its proteolytic cleavage in 16HBE cells

2169 | Dec 31 2016

Cheng J et al. demonstrated that MGMT might turn into a DNA damage promoter by forming DPC when exposed to HN2. [Read the Full Post]

AKT and 14-3-3 Regulate Notch4 Nuclear Localization

3158 | Dec 29 2016

Ramakrishnan G, et al.'s findings provide a novel mechanism for Notch4-ICD regulation, suggesting a negative regulatory role for the PI3K-AKT pathway in Notch4 nuclear signaling. [Read the Full Post]

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

1468 | Dec 17 2016

Lu YX et al. suggested 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]

Assessment of the chemotherapeutic potential of a new camptothecin derivative, ZBH-1205

2176 | Dec 10 2016

Wu D et al. found that ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials. [Read the Full Post]

Receptor for Activated C Kinase 1 (RACK1) Promotes Dishevelled Protein Degradation via Autophagy and Antagonizes Wnt Signaling

1884 | Sep 28 2016

Cheng M et al. revealed a novel regulatory function of RACK1 in Wnt signaling by modulating Dvl stability. [Read the Full Post]

ERK induces degradation of tumor suppressor FBW7 in pancreatic cancer

6693 | Mar 18 2015

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

MiR-146-NF-κB pathway is a key axis in the regulation of FOXP3-deficient prostate cancers

3558 | Mar 12 2015

Liu et al. from University of Alabama at Birmingham reveal FOXP3-microRNA-146(miR-146)-NF-κB axis as a critical signaling pathway in regulating the survival of prostate cancer cells both in vitro and in vivo. [Read the Full Post]

RIP1, a novel oncogenic driver in melanoma

4539 | Mar 06 2015

u et al. found that RIP1 plays a role as an oncogenic driver in human melanoma. [Read the Full Post]

Inhibition of proteasome restores bortesomib-induced thrombocytopenia

9366 | Feb 10 2015

Shi et al. reported clinical proteasome inhibitor enable to block proplatelet formation by megakaryocytes in human and mouse model. [Read the Full Post]

Proteasome inhibitor salvages messense mutated dysferlin in muscular dystrophy patients

3550 | Feb 09 2015

Azakir et al. demonstrated proteasome inhibitor is able to increase the expression of messense mutated dyferlin, and restores the membrane resealing capacity of myoblasts. [Read the Full Post]

Suppressing HER3 signaling by interfering with its Sec61-dependent contranlational translocation

3421 | Feb 03 2015

Ruiz-Saenz et al. demonstrated a novel approach specifically reduces HER3 expression. [Read the Full Post]

Unexpected role of Notch signaling on directing the trophectoderm lineage in the mouse blastocyst

5884 | Jan 30 2015

Rayon et al. showed that Notch signaling plays a key role in mediating TE-specific expression of Cdx2, though interaction with the transcription factor TEAD4. [Read the Full Post]

The mechanism of action of new antitumor drug FL118

3704 | Dec 25 2014

Recently, Ling et al. demonstrated the mechanism of FL118 antitumor action. The drug suppress tumor growth by promotion of MdmX degradation and consequent stimulation of p53 signaling. [Read the Full Post]

The Notch signaling controls maintenance of memory CD4+ T cells

9143 | Dec 16 2014

Recently, Maekawa et al. demonstrated Notch signaling is important for the survival of memory CD4+ T cells by regulating glucose uptake. [Read the Full Post]

Hippo signaling mediates hypoxia tumorgenesis via SIAH2

3956 | Dec 05 2014

Ma et al. gives a insight into the mechanism of Hippo signaling by investigating the pathway deactivation induced by hypoxia. [Read the Full Post]

MeCP2 S421 phosphorylation mediates neurogenesis via Notch signaling pathway

7904 | Dec 04 2014

Li et al. identified the Notch signaling is involved in the regulation of MeCP2 S421 phosphorylation other than neuronal activity. [Read the Full Post]

Notch signaling acts as a key regulator in generation of neurons from neural precursor cells

5158 | Oct 23 2014

Notch signaling plays a central role before asymmetric division and in the fate of Drosophila melanogaster neural precursor cells. It also acts as a critical factor in Numb distribution in neural precursor cells before cleavage. [Read the Full Post]

Not all DUBs are equal

3526 | Mar 21 2014

Bortezomib (PS-341) is a potent 20S proteasome inhibitor with Ki of 0.6 nM. [Read the Full Post]

AGI5198 is the first highly potent and selective mutant IDH1 inhibitor

3240 | Mar 07 2014

AGI-5198, potently inhibits mutant IDH1 (R132H-IDH1 and R132C-IDH1), but not wildtype IDH1 (IC50 > 100 μM) or any of IDH2 isoforms (R140Q, R172K, wildtype) (IC50 > 100 μM) [Read the Full Post]

MLN9708 is a proteasome inhibitor and is the first to enter clinical trials

3335 | Feb 19 2014

MLN9708 is a selective, orally bioavailable, second-generation proteasome inhibitor. [Read the Full Post]

RO4929097 is a small molecule gamma secretase inhibitor

3309 | Feb 13 2014

RO4929097 is a γ secretase inhibitor with IC50 of 4 nM, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. [Read the Full Post]

Bortezomib is the first therapeutic proteasome inhibitor to be tested in humans

2971 | Jan 26 2014

Bortezomib, a boronic acid dipeptide, is a highly selective, reversible inhibitor of the 26S proteasome which primarily functions in the degradation of mis-folded proteins and is essential for the regulation of the cell cycle. [Read the Full Post]

Nutlin 3 is a cis imidazoline analog

3914 | Jan 26 2014

Nutlin-3 is a potent and selective Mdm2 (RING finger-dependent ubiquitin protein ligase for itself and p53) antagonist with IC50 of 90 nM; stabilizes p73 in p53-deficient cells. [Read the Full Post]

MLN9708 is a proteasome inhibitor and is the first to enter clinical trials as an oral preparation

2817 | Jan 14 2014

MLN9708 immediately hydrolyzed to MLN2238, the biologically active form, on exposure to aqueous solutions or plasma. [Read the Full Post]

Bortezomib is a highly selective reversible inhibitor of the 26S proteasome

2939 | Jan 09 2014

Bortezomib, a boronic acid dipeptide, is a highly selective, reversible inhibitor of the 26S proteasome which primarily functions in the degradation of mis-folded proteins and is essential for the regulation of the cell cycle. [Read the Full Post]

Tipifarnib is a farnesyltransferase inhibitor

2428 | Dec 18 2013

Tipifarnib (R115777) is a potent and specific farnesyltransferase (FTase) inhibitor with IC50 of 0.6 nM, its anti-proliferative effects are most prominent in H-ras or N-ras mutant cells. [Read the Full Post]

Bortezomib is the first clinically approved proteasome inhibitor for treating multiple human malignancies

2974 | Dec 16 2013

Bortezomib, a boronic acid dipeptide, is a highly selective, reversible inhibitor of the 26S proteasome which primarily functions in the degradation of mis-folded proteins and is essential for the regulation of the cell cycle. [Read the Full Post]

Nutlin 3 inhibits the interaction between the proteins p53 and MDM2

3805 | Nov 29 2013

Nutlin-3 is a potent and selective Mdm2 (RING finger-dependent ubiquitin protein ligase for itself and p53) antagonist with IC50 of 90 nM; stabilizes p73 in p53-deficient cells. [Read the Full Post]

Bortezomib is the first therapeutic proteasome inhibitor

3021 | Nov 26 2013

Bortezomib (PS-341) is a potent 20S proteasome inhibitor with Ki of 0.6 nM. [Read the Full Post]

BMS 790052 is the most potent hepatitis C virus inhibitor

3970 | Nov 13 2013

BMS-790052 is a highly selective inhibitor of HCV NS5A with EC50 of 9-50 pM, for a broad range of HCV replicon genotypes and the JFH-1 genotype 2a infectious virus in cell culture. Phase 3. [Read the Full Post]

FK866 has been shown to induce apoptosis by non competitive

2772 | Nov 12 2013

APO866 effectively inhibits nicotinamide phosphoribosyltransferase (NMPRTase) with IC50 of 0.09 nM. Phase 1/2. [Read the Full Post]

Semagacestat was compared with placebo in more than 2600 patients

2986 | Oct 21 2013

Semagacestat reduces the secretion of Aβ42, Aβ40 and Aβ38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium [Read the Full Post]

Nutlin3 inhibits the MDM2 p53 interaction and activates p5

3733 | Sep 26 2013

Nutlin-3 is a potent and selective Mdm2 (RING finger-dependent ubiquitin protein ligase for itself and p53) antagonist with IC50 of 90 nM; stabilizes p73 in p53-deficient cells. [Read the Full Post]

PD168393 is a strongly effective EGFR inhibitors

2921 | Jul 18 2013

PD 168393 is docked into the ATP binding pocket of EGFR TK. PD168393 completely suppresses EGF-dependent receptor autophosphorylation in A431 cells during continuous exposure, with continous suppression even after 8 hr in compound-free medium. [Read the Full Post]

MG132 is a specific potent reversible and cell permeable proteasome inhibitor

2731 | Jun 20 2013

MG-132 displays >1000 times more activity than ZLLal in inhibiting the ZLLL-MCA-degrading activity of 20S proteasome with IC50 of 100 nM versus 110 μM. MG-132 also inhibits calpain with IC50 of 1.2 μM. [Read the Full Post]

LY2484595 is one of two CETP inhibitors currently being evaluated

2454 | May 02 2013

LY2484595 results in 98.4%, 98.6%, and 18.4% inhibition of CETP activity at 4 hours, 8 hours and 24 hours post dose respectively in human ApoAI and CETP double transgenic mice. [Read the Full Post]

MG132 is a specific potent reversible and cell permeable proteasome inhibitor

3331 | Apr 22 2013

MG-132 displays >1000 times more activity than ZLLal in inhibiting the ZLLL-MCA-degrading activity of 20S proteasome with IC50 of 100 nM versus 110 μM. MG-132 also inhibits calpain with IC50 of 1.2 μM. MG-132 induces neurite outgrowth in PC12 cells at an optimal concentration of 20 nM. [Read the Full Post]

PS341 was tested in a small Phase I clinical trial on patients with multiple myeloma cancer

2455 | Mar 25 2013

PS-341 is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma[1] and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease. [Read the Full Post]

Telaprevir is an associate of a class of antiviral drugs

4092 | Mar 21 2013

Telaprevir is an associate of a class of antiviral drugs called protease inhibitors. Especially, telaprevir prevents the hepatitis C viral enzyme NS3.4A serine protease. Telaprevir is just indicated for use against hepatitis d genotype 1 viral infections and hasnt been which can have an impact on or being protected when employed for other genotypes of the herpes virus. The standard therapy of ribavirin and pegylated interferon is less successful on genotype 1 and a welcome addition is offered by telaprevir to the treatment of this genotype. [Read the Full Post]

MDV3100 is an androgen receptor antagonist

2180 | Jan 15 2013

Increased protein levels and kinase activities of Src family kinases have been observed in a wide diversity of human cancers, including melanoma, breast, ovarian, and lung cancer . The prototype SFK is c-Src, MDV3100 which is a protein tyrosine kinase from which the oncogenic viral Src is derived . [Read the Full Post]

DPP 4 is regulated transcriptionally RGS4

2767 | Dec 04 2012

[Read the Full Post]

Gamma Secretase were grown in 5 ml of medium

4918 | Nov 28 2012

The cells were pelleted by centrifugation, the medium was Gamma Secretase removed with the drug, and the cells were washed washed with sterile PBS and centrifuged again. [Read the Full Post]

Telaprevir has very poor penetration of the blood brain

5146 | Nov 15 2012

The principal metabolic fate of loperamide in humans involves oxidative N dealkylation to N demethyl loperamide as the principal metabolite. In human liver microsomes, cytochrome P450 3A4 appears to be the major isozyme responsible for loperamide metabolism, with minor contributions from CYP2B6 [Read the Full Post]

DPP-4 of cisplatin ECCC involved downregulate

3211 | Nov 02 2012

Th Rho kinase and PI-3-kinase in ECCC completely yet Constantly described. In this study we have tried to determine whether to f HA and CD44 on Rho kinase and PI-3-kinase signaling progression ECCC Interact rdern [Read the Full Post]

BMS-790052 A Tr droplets With twice as many cells pressed

4033 | Oct 23 2012

BMS-790052 A Tr droplets With twice as many cells pressed agA Tr droplets, With twice as many cells pressed against the heart tee h Here cAMP concentration against each other, the proportion of droplets tears reported a positive response [Read the Full Post]

BORTEZOMIB: AN INHIBITOR OF PROTEASOMAL DEGRADATION

2437 | Aug 28 2012

BORTEZOMIB Proteasomes are one of the very important small organelles present in the cell. They have an important role in cell cycle regulation by degrading un-necessary proteins present in the cell. Sometimes in cancerous cells, the proteins that play a role in inhibiting un-regulated proliferation of cells are degraded by proteasomes. Inhibition of proteasomes in order to inhibit un-regulated growth is an attractive target in cancer therapy. Different proteasome inhibiting compounds have been used conventionally for the treatment of cancer e.g.,green tea having Epigallocatechin-3-gallate (EGCG), Salinosporamide-A and Disulfiram. Bortezomib is the first proteasomal inhibitor that has got approval for clinical studies for the treatment of cancer. [Read the Full Post]

BORTEZOMIB: AN ANTI-PROTEASOMAL AGENT

3616 | Jul 01 2012

BORTEZOMIB: INTRODUCTION In cell among the tiny organelles proteasomes are the foremost vital ones. They play necessary role in the correct regulation of the cell cycle by removing the proteins that don't seem to be necessary for cell. In cancer cell it rarely happens that the proteins which are involved in the controlling the dysregulated growth of the cells are excised by proteasomes. A promising target for the therapy of cancer is to inhibit proteasomes so that the uncontrolled growth is inhibited. A variety of compounds were typically used for cancer therapy that inhibits proteasomes. Among them EGCG additionally referred to as Epigallocatechin-3-gallate, Disulfiram and Salinosporamide-A that are present in green tea were used. The primary inhibitor of proteasomes that got approved to enter clinical trials for cancer therapy is Bortezomib. [Read the Full Post]

BORTEZOMIB: AN ANTI-PROTEIN DEGRADATION AGENT

4520 | Jun 20 2012

BORTEZOMIB Proteasomes belong to one of the important small organelles present in cell. Cell cycle is regulated by these proteasomes as they remove any unnecessary protein from cell. Usually during the cancer state the proteins which inhibit uncontrolled cell development of cancer are chopped down by these proteasomes. To stop chop these abnormal proteins properly inhibition of proteasomes is necessary which offers a good target for cancer therapy. For cancer treatment a lot of various compounds are being employed that cause proteasomes inhibition for example e.g., green tea having Epigallocatechin-3-gallate (EGCG), Salinosporamide-A and Disulfiram. Bortezomib was entitled to be first inhibitor that got approval to enter clinical studies for treatment of cancer. [Read the Full Post]

BORTEZOMIB; INHIBITING PROTEIN DEGRADATION

3703 | May 17 2012

BORTEZOMIB Poteasomes are one of the very important small organelles present in the cell. They have an important role in cell cycle regulation by degrading un-necessary proteins present in the cell. Sometimes in cancerous cells, the proteins that play a role in inhibiting un-regulated proliferation of cells are degraded by proteasomes. Inhibition of proteasomes in order to inhibit un-regulated growth is an attractive target in cancer therapy. Different proteasome inhibiting compounds have been used conventionally for the treatment of cancer e.g., green tea having Epigallocatechin-3-gallate (EGCG), Salinosporamide-A and Disulfiram. Bortezomib is the first proteasomal inhibitor that has got approval for clinical studies for the treatment of cancer. [Read the Full Post]

BORTEZOMIB – PROTEASOMAL INHIBITOR

3351 | Apr 26 2012

BORTEZOMIB: One of the most important categories of enzymes in the cell is the protein degrading enzymes called as proteosomes. They degrade all types of un-wanted proteins in the cells hence can regulate some important pathways in the cells like gene expression and cell cycle. The compounds which obstruct the activity of these enzymes play an important role in process of inhibition of degradation of cancer inhibiting proteins. Due to these properties proteosome inhibiting molecules like EGCG (Epigallocatechin-3-gallate) known as green tea as well, Disulfiram and Salinosporamide-A have been found to use for treatment of cancer. The first approved proteosomal inhibiting drug for clinical studies is Bortezomib and it is a very famous inhibitor of this class of enzymes. [Read the Full Post]

BORTEZOMIB – A PROTEASOME INHIBITOR

3108 | Apr 10 2012

BORTEZOMIB: There are different enzymes are present in the cell and amongst these enzymes Proteasomes are large enzymes which play function of degrading un-wanted proteins of cells, therefore these enzymes regulate some of the most important pathways including cell cycle and genetic expression. Those compounds which hinder the actions of these proteasomes play important functions in the process of inhibiting the degradation of tumor inhibiting proteins. Because of these properties the proteasome inhibitors such as EGCG (Epigallocatechin-3-gallate) also known as green tea, Salinosporamide-A and Disulfiram have been applied for cancer treatment. Bortezomib is the first approved proteasome inhibitor for clinical trials; this is the most famous inhibitor of this category. [Read the Full Post]

RO4929097 – CHECKS NOTCH SIGNALING IN CANCERS

5352 | Mar 20 2012

RO4929097: A GAMMA SECRETASE INHIBITOR: Among well known proteases Gamma secretase is one which is made up of various subunits. This is present in the membrane hence is a protein in membrane which is also capable of cleaving certain transmembrane proteins therefore also known as the intramembrane protease. In case of Alzheimer’s disease amyloid plaques are formed in brain, these plaques are resulted due to the amyloid beta peptide and these peptides are produced due to the action of gamma secretase, this is one of the well known examples of this protease. Presently, we are focusing on the important role of gamma secretase in the Notch protein processing. In case of many cancers and tumors this Notch protein signaling is found to be abnormal, therefore the arresting of this pathway can be an authentic way to get rid of abnormal cell growth. In the light of this idea a novel RO4929097 gamma secretase inhibitor is discovered. The inhibitory effect of this inhibitor has been confirmed by various methods like western blotting. [Read the Full Post]

BORTEZOMIB – THE FIRST PROTEASOME INHIBITOR

2578 | Mar 19 2012

Introduction: Inhibition of the Proteasomes In the cellular environment there is a continuous movement of cells through cycles of life and death. Material is up taken and used to create new cells or energy, while protein signaling cascades regulate everything so that the host organism survives. However, during these essential processes proteins become damaged, unraveled or simply surplus to requirements, in this situation there exists clean up mechanisms to recycle as much material as possible. The major (>80%) pathway for this process is the proteasome pathway which in conjunction with the Ubiquitin pathway performs clean up routines in the cellular environment. The proteasome is a tubular protein sealed with another protein containing a tyrosine kinase domain. This tubular protein allows “tagged” protein to enter and bind within the tube section. Then catalytic activity begins to dismantle the protein and pass subunits out into the cytosole for reuse. Protein are recognized for destruction due to the actions of the Ubiquitin protein kinases. [Read the Full Post]

RO4929097 – TARGETING NOTCH SIGNALING IN CANCER

6024 | Mar 13 2012

RO4929097: INHIBIT GAMMA SECRETASE: Gamma secretase is famous protease consists of several subunits complex. This enzyme is also recognized as inter-membrane protease as it cuts trans-membrane proteins. The most eminent gamma secretase example is breakage of amyloid precursor, a protein to produce amyloid beta peptide which is involved in the formation of amyloid plaques in patient’s brain who suffer with Alzheimer’s disease. In the present situation though, we concentrate on the key role of gamma secretase in the Notch protein processing. It has been found as there is link between anomalous notch signaling and many cancers. Hence the idea of targeting those enzymes which are responsible for the processing of Notch protein became the reason of RO4929097 gamma secretase inhibitor discovery. The inhibiting Notch signaling by using RO4929097 GS inhibitor has been confirmed by protein estimation methods like Biuret method etc. [Read the Full Post]

RO4929097 – CONTROLLING NOTCH SIGNALING IN TUMORS

6148 | Mar 13 2012

Introduction: Gamma secretase Inhibition Gamma secretase is an internal protease enzyme that is a complex of a number of subunits. Its mode of action is to cleave proteins that lie within the membrane-spanning domain, these include the amyloid precursor protein (APP) and the Notch. The Notch signaling pathway processes four different Notch receptors (1, 2, 3 and 4) which span the cell membrane. Upon extracellular interaction with a substrate protein the internal domain is released. This section of the protein then induced a signaling cascade within the cell nucleus to alter gene expression. The function of the various NOTCH proteins is varied but in terms of cancer notch receptors have been demonstrated to be down regulated in basal cells carcinomas and cervical cancers. Notch 1 over-expression is associated with acute T cell leukemia and breast cancer, Notch 3 receptor is over-expressed in 20% of ovarian cancers [5-7] while overexpression of Notch 4 is evident in murine models of breast cancer. The field of research into NOTCH signaling is vast and beyond the scope of this document, simple put there existed evidence that inhibition of aberrant NOTCH over-expression would be an ideal target for chemotherapeutic activity. The development of inhibitors which would affect the action of NOTCH led to the targeting of the Gamma secretase enzyme. Developed by Roche the RO4929097 gamma secretase inhibitor represents a potent novel small molecule that is orally bioavailable. [Read the Full Post]

Yin, L., O. C. Velazquez, et al. (2010). "Notch signaling: emerging molecular targets for cancer therapy." Biochem Pharmacol 80(5): 690-701.

5228 | Jul 13 2011

This article is a review which give a presentation of Notch signal pathway and how the researchers target Notch signal pathway for a cancer therapy. [Read the Full Post]