Blog of Signaling Pathways

Flavopiridol enhances ABT-199 sensitivity in unfavourable-risk multiple myeloma cells in vitro and in vivo

364 views | Jul 12 2019

Zhou L et al. argue that CDK9 inhibitors, for example, FP may increase the antimyeloma activity of ABT-199, including in unfavourable-risk MM minimally responsive to ABT-199 alone. [Read the Full Post]

Therapeutics targeting Bcl-2 in hematological malignancies

370 views | Jul 12 2019

Ruefli-Brasse A et al. review recent progress in direct and selective targeting of Bcl-2 family proteins for cancer therapy and the search for rationale combinations. [Read the Full Post]

A patent review of arginine methyltransferase inhibitors (2010-2018)

733 views | Jul 10 2019

Li X et al. summarized the updated patented inhibitors targeting PRMTs from 2010 to 2018. The authors illustrate the chemical structures, molecular mechanism of action, pharmacological activities as well as the potential clinical application including combination therapy and biomarker-guided therapy. PRMT inhibitors in clinical trials are also highlighted. The authors provide a future perspective for further development of potent and selective PRMT inhibitors. [Read the Full Post]

Airway Progenitor Clone Formation Is Enhanced by Y-27632-Dependent Changes in the Transcriptome

1226 views | Jul 10 2019

Reynolds SD et al. concluded that Y-27632 fundamentally alters cell-cell and cell-ECM interactions, which preserves basal progenitor cells and allows greater cell amplification. [Read the Full Post]

Characterization of Three Novel H3F3A-mutated Giant Cell Tumor Cell Lines and Targeting of Their Wee1 Pathway

499 views | Jul 09 2019

Lübbehüsen C et al, offered valuable new tools for GCTB studies and presents a description of novel biomarkers and molecular targeting strategies. [Read the Full Post]

Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease

520 views | Jul 09 2019

Gryka RJ et al. indicated vorapaxar provides clinicians with a novel mechanism of action to further reduce the burden of ischemic heart disease. Identification of patients with a high ischemic risk and low bleeding risk would enable clinicians to maximize the utility of this unique agent. [Read the Full Post]

JAK1/2 Inhibitors AZD1480 and CYT387 Inhibit Canine B-Cell Lymphoma Growth by Increasing Apoptosis and Disrupting Cell Proliferation

880 views | Jul 08 2019

Lu Z et al. justified further phase I/II clinical investigations of the safety and efficacy of JAK1/2 inhibitors in canine DLBCL and suggest new opportunities for novel anticancer therapies. [Read the Full Post]

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

556 views | Jul 08 2019

Swords RT et al. indicated that administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. [Read the Full Post]

Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study

667 views | Jul 07 2019

Fennell DA et al. indicated that neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM. Defactinibcannot be recommended as maintenance therapy for advanced MPM. [Read the Full Post]

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

757 views | 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]

Associated-Extraction Efficiency of Six Cyclodextrins on Various Flavonoids in Puerariae Lobatae Radix

539 views | Jul 05 2019

Feng T et al. indicated that CDs, especially SBE-β-CD, have a promising application for the associated-extraction of flavonoids from PLR. [Read the Full Post]

Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers

771 views | Jul 03 2019

Katoh M indicated that SMO inhibitors can remodel the immunosuppressive TME that is dominated by M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells and regulatory T cells, and thus, a Phase I/II clinical trial of the immune checkpoint inhibitor pembrolizumab with or without vismodegib in BCC patients is ongoing. [Read the Full Post]

Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage

933 views | Jul 02 2019

Villarreal S et al. showed the absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Aβ peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients. These data will be compared with longitudinal MRI profiles from ongoing clinical trials. [Read the Full Post]

In Vitro Activity of Sitafloxacin and Additional Newer Generation Fluoroquinolones Against Ciprofloxacin-Resistant Neisseria gonorrhoeae Isolates

475 views | Jul 01 2019

Hamasuna R et al. indicated that sitafloxacin should not be considered for empirical first-line monotherapy of gonorrhea. However, sitafloxacin could be valuable in a dual antimicrobial therapy and for cases with ceftriaxone resistance or allergy. [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

713 views | 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]

Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects

818 views | Jun 30 2019

Tran P et al. presented the results of human oral absorption, distribution, metabolism, excretion (ADME) and in vitro studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans. [Read the Full Post]

First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity

412 views | Jun 30 2019

Gan HK et al. showed the tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC. [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

314 views | 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]

Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies

634 views | Jun 28 2019

Lang L et al. indicated their aim is to pinpoint the potential of FGFR4 as a therapeutic target and identify new avenues for advancing future research in the field. [Read the Full Post]

Building on the success of osimertinib: achieving CNS exposure in oncology drug discovery

720 views | Jun 27 2019

Colclough N et al. demonstrated how these innovative kinase inhibitors were recognized as brain penetrant and outline our view of experimental approaches and strategies that can facilitate the discovery of new brain-penetrant therapies for the treatment of primary and secondary CNS malignancies as well as other CNS disorders. [Read the Full Post]