Structure-based design and discovery of potent and selective KDM5 inhibitors.

Zhe Nie, Lihong Shi, Chon Lai, Shawn M O'Connell, Jiangchun Xu, Ryan K Stansfield, David J Hosfield, James M Veal, Jeffrey A Stafford

Journal: Bioorganic & medicinal chemistry letters 2018;28(9):1490-1494

PMID: 29627262

Full Text on Elsevier Science View on PubMed

Abstract

Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1.

Address: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, USA. Electronic address: [email protected].; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, USA.; Ben May Department for Cancer Research, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.

DOI: 10.1016/j.bmcl.2018.03.083