| Literature DB >> 27214401 |
Maia Vinogradova1, Victor S Gehling2, Amy Gustafson1, Shilpi Arora2, Charles A Tindell1, Catherine Wilson1, Kaylyn E Williamson2, Gulfem D Guler1, Pranoti Gangurde2, Wanda Manieri2, Jennifer Busby2, E Megan Flynn1, Fei Lan2, Hyo-Jin Kim1, Shobu Odate2, Andrea G Cochran1, Yichin Liu1, Matthew Wongchenko1, Yibin Yang1, Tommy K Cheung1, Tobias M Maile1, Ted Lau1, Michael Costa1, Ganapati V Hegde1, Erica Jackson1, Robert Pitti1, David Arnott1, Christopher Bailey2, Steve Bellon2, Richard T Cummings2, Brian K Albrecht2, Jean-Christophe Harmange2, James R Kiefer1, Patrick Trojer2, Marie Classon1.
Abstract
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.Entities:
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Year: 2016 PMID： 27214401 DOI： 10.1038/nchembio.2085
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040