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Ref Type Journal Article
PMID (30253346)
Authors Wang B, Wu J, Wu Y, Chen C, Zou F, Wang A, Wu H, Hu Z, Jiang Z, Liu Q, Wang W, Zhang Y, Liu F, Zhao M, Hu J, Huang T, Ge J, Wang L, Ren T, Wang Y, Liu J, Liu Q
Title Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor.
Journal European journal of medicinal chemistry
Vol 158
Issue
Date 2018 Oct 05
URL
Abstract Text Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound 40 (JSH-150), which exhibited an IC50 of 1 nM against CDK9 kinase in the biochemical assay and achieved around 300-10000-fold selectivity over other CDK kinase family members. In addition, it also displayed high selectivity over other 468 kinases/mutants (KINOMEscan S score(1) = 0.01). Compound 40 displayed potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer as well as leukemia cell lines. It could dose-dependently inhibit the phosphorylation of RNA Pol II, suppress the expression of MCL-1 and c-Myc, arrest the cell cycle and induce the apoptosis in the leukemia cells. In the MV4-11 cell-inoculated xenograft mouse model, 10 mg/kg dosage of 40 could almost completely suppress the tumor progression. The high selectivity and good in vivo PK/PD profile suggested that 40 would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
JSH-150 JSH-150 7 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
JSH-150 CDK9 Inhibitor 16 JSH-150 selectively inhibits CDK9, potentially resulting in increased cell-cycle arrest and decreased proliferation of tumor cells (PMID: 30253346).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown melanoma not applicable JSH-150 Preclinical - Cell culture Actionable In a preclinical study, JSH-150 inhibited proliferation of a melanoma cell line in culture (PMID: 30253346). 30253346
Unknown unknown acute myeloid leukemia not applicable JSH-150 Preclinical - Cell line xenograft Actionable In a preclinical study, JSH-150 induced cell-cycle arrest and inhibited proliferation of acute myeloid leukemia cell lines in culture, and inhibited tumor progression in xenograft models (PMID: 30253346). 30253346
Unknown unknown B-cell lymphoma not applicable JSH-150 Preclinical - Cell culture Actionable In a preclinical study, JSH-150 inhibited proliferation of a B-cell lymphoma cell line in culture (PMID: 30253346). 30253346
Unknown unknown neuroblastoma not applicable JSH-150 Preclinical - Cell culture Actionable In a preclinical study, JSH-150 inhibited proliferation of a neuroblastoma cell line in culture (PMID: 30253346). 30253346
Unknown unknown chronic lymphocytic leukemia not applicable JSH-150 Preclinical - Cell culture Actionable In a preclinical study, JSH-150 induced cell-cycle arrest and inhibited proliferation of chronic lymphocytic leukemia cell lines in culture (PMID: 30253346). 30253346
Unknown unknown colon cancer not applicable JSH-150 Preclinical - Cell culture Actionable In a preclinical study, JSH-150 inhibited proliferation of a colon cancer cell line in culture (PMID: 30253346). 30253346
Unknown unknown gastrointestinal stromal tumor not applicable JSH-150 Preclinical - Cell culture Actionable In a preclinical study, JSH-150 inhibited proliferation of a gastrointestinal stromal tumor cell line in culture (PMID: 30253346). 30253346