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

  • Bioorg Med Chem Lett. 2018 May 15;28(9):1490-1494. doi: 10.1016/j.bmcl.2018.03.083.
Zhe Nie  1 ,  Lihong Shi  2 ,  Chon Lai  2 ,  Shawn M O'Connell  2 ,  Jiangchun Xu  2 ,  Ryan K Stansfield  2 ,  David J Hosfield  3 ,  James M Veal  2 ,  Jeffrey A Stafford  2
Affiliations
  • 1. Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, USA. Electronic address: [email protected].
  • 2. Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, USA.
  • 3. Ben May Department for Cancer Research, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
PMID: 29627262 DOI: 10.1016/j.bmcl.2018.03.083
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.

Keywords
Epigenetics; Histone lysine demethylase; KDM5; Structure-based design; Tri-methylated H3K4.
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