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

doi:10.1016/j.bmcl.2018.03.083

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. Epub 2018 Mar 30.

Authors

Zhe Nie¹, Lihong Shi², Chon Lai², Shawn M O'Connell², Jiangchun Xu², Ryan K Stansfield², David J Hosfield³, James M Veal², Jeffrey A Stafford²

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Female
Humans
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
Jumonji Domain-Containing Histone Demethylases / metabolism
MCF-7 Cells
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / pathology
Models, Molecular
Molecular Structure
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / metabolism
Repressor Proteins / antagonists & inhibitors*
Repressor Proteins / metabolism
Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*
Retinoblastoma-Binding Protein 2 / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
Nuclear Proteins
Repressor Proteins
Jumonji Domain-Containing Histone Demethylases
KDM5A protein, human
KDM5B protein, human
Retinoblastoma-Binding Protein 2