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Blog of Signaling Pathways

Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-deficient Breast Cancer

221 views | Jul 22 2019

Belz JE et al. demonstrated that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors. [Read the Full Post]

Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island

252 views | Jul 21 2019

Arriola Apelo SI et al. discuss recent advances in understanding the molecular and physiological effects of rapamycin treatment, and we discuss how the use of alternative rapamycin treatment regimens or rapamycin analogs has the potential to mitigate the deleterious side effects of rapamycin treatment by more specifically targeting mTORC1. Although the side effects of rapamycin are still of significant concern, rapid progress is being made in realizing the revolutionary potential of rapamycin-based therapies for the treatment of diseases of aging. [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

204 views | 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]

Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs

183 views | Jul 18 2019

Patwardhan PP et al. suggested that PLX3397 is superior to imatinib in the treatment of MPNSTs, and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease. [Read the Full Post]

Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors

0 views | Jul 18 2019

Naujok O et al. indicated that out of the four tested GSK3 inhibitors, only CHIR-99021 and CHIR-98014 proved to be potent pharmacological activators of the Wnt/beta-catenin signaling pathway. But only in the case of CHIR-99021 high potency was combined with very low toxicity. [Read the Full Post]

Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development

167 views | Jul 17 2019

Clark AS et al. indicated that palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way. [Read the Full Post]

Inhibition of Bcl-2/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice

155 views | Jul 16 2019

Pan J et al. demonstrated that PF can be reversed by a senolytic drug such as ABT-263 after it becomes a progressive disease. Therefore, ABT-263 has the potential to be developed as a new treatment for PF. [Read the Full Post]

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

219 views | Jul 16 2019

Honigberg LA et al. support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway. [Read the Full Post]

A novel antiandrogen, Compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth in vitro and in vivo

222 views | Jul 15 2019

Kuruma H et al. provided a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors. [Read the Full Post]

Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors

143 views | Jul 15 2019

Zhu Y et al. showed the hypothesis-driven, bioinformatics-based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type-specific senolytic agents. [Read the Full Post]

The PARP inhibitor AZD2281 (Olaparib) induces autophagy/mitophagy in BRCA1 and BRCA2 mutant breast cancer cells

188 views | Jul 14 2019

Arun B et al. indicated that the patients with BRCA1 allelic loss may also benefit from PARP inhibitor therapy if BRCA is further inhibited. [Read the Full Post]

BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib

589 views | Jul 14 2019

Faraoni I et al. showed the high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and/or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy. [Read the Full Post]

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

186 views | Jul 13 2019

Boscolo E et al. demonstrated that cells from KLA patient lesions are highly proliferative and the PI3K-AKT-mTOR and MAPK pathways are promising therapeutic targets. [Read the Full Post]

Antiproliferative and Antimigratory Effects of a Novel YAP-TEAD Interaction Inhibitor Identified Using in Silico Molecular Docking

222 views | Jul 13 2019

Smith SA et al. reported the identification of a novel compound (CPD3.1) with the ability to disrupt YAP-TEAD protein-protein interaction and inhibit TEAD activity, cell proliferation, and cell migration. The YAP-TEAD complex is a viable drug target, and CPD3.1 is a lead compound for the development of more potent TEAD inhibitors for treating cancer and other hyperproliferative pathologies. [Read the Full Post]

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

153 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

151 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)

252 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

410 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

201 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

181 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]