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

• Published in: Bioorganic & medicinal chemistry letters 2018-05, Vol.28 (9), p.1490-1494
• Main Authors: Nie, Zhe, Shi, Lihong, Lai, Chon, O'Connell, Shawn M., Xu, Jiangchun, Stansfield, Ryan K., Hosfield, David J., Veal, James M., Stafford, Jeffrey A.
• Format: Article
• Language: English
• Subjects: 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; Epigenetics; Female; Histone lysine demethylase; Humans; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors; Jumonji Domain-Containing Histone Demethylases - metabolism; KDM5; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; MCF-7 Cells; 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; Structure-based design; Tri-methylated H3K4
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.03.083

[Display omitted] •KDM5A/5B have been identified as potential anti-cancer drug targets.•Compound 33 is an orally available, potent inhibitor of KDM5A/5B with promising selectivity.•Compound 33 promotes H3K4me3 increases both in vitro and in vivo.•Compound 33 is a valuable tool compound to interrogate the biology of KDM5A/5B. 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.