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Ref Type Journal Article
PMID (27214401)
Authors Vinogradova M, Gehling VS, Gustafson A, Arora S, Tindell CA, Wilson C, Williamson KE, Guler GD, Gangurde P, Manieri W, Busby J, Flynn EM, Lan F, Kim HJ, Odate S, Cochran AG, Liu Y, Wongchenko M, Yang Y, Cheung TK, Maile TM, Lau T, Costa M, Hegde GV, Jackson E, Pitti R, Arnott D, Bailey C, Bellon S, Cummings RT, Albrecht BK, Harmange JC, Kiefer JR, Trojer P, Classon M
Title An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells.
Journal Vol Issue Date Pages Journal Short Title
Nature chemical biology 12 7 2016 Jul 531-8 Nat Chem Biol
URL
Abstract Text The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). Here we report the discovery and characterization of the specific KDM5 inhibitor CPI-455. The crystal structure of KDM5A revealed the mechanism of inhibition of CPI-455 as well as the topological arrangements of protein domains that influence substrate binding. CPI-455 mediated KDM5 inhibition, elevated global levels of H3K4 trimethylation (H3K4me3) and decreased the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents. These findings show that pretreatment of cancer cells with a KDM5-specific inhibitor results in the ablation of a subpopulation of cancer cells that can serve as the founders for therapeutic relapse.

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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
CPI-455 CPI-455 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CPI-455 CPI-455 is an inhibitor of KDM5A, KDM5B, and KDM5C, which may reduce cell survival, in particular those cells that are considered drug resistant (PMID: 27214401, PMID: 31238504).
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