2. Academic Validation
  3. Structure-based design and discovery of potent and selective KDM5 inhibitors

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

Affiliations

  • 1 Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, USA. Electronic address: znie@celgene.com.
  • 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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