Identification of potent, selective KDM5 inhibitors. Issue 17 (1st September 2016)

• Record Type: Journal Article
• Authors: Gehling, Victor S.; Bellon, Steven F.; Harmange, Jean-Christophe; LeBlanc, Yves; Poy, Florence; Odate, Shobu; Buker, Shane; Lan, Fei; Arora, Shilpi; Williamson, Kaylyn E.; Sandy, Peter; Cummings, Richard T.; Bailey, Christopher M.; Bergeron, Louise; Mao, Weifeng; Gustafson, Amy; Liu, Yichin; VanderPorten, Erica; Audia, James E.; Trojer, Patrick; Albrecht, Brian K.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 17(2016)
• Page Start: 4350
• Page End: 4354
• Publication Date: 2016-09-01
• Subjects: Histone lysine demethylase -- KDM5 -- JARID1 -- Epigenetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.07.026
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound1, a hit initially identified against KDM4C. Compound1 was optimized to afford compound20, a 10 nM inhibitor of KDM5A. Compound20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization.