Design and evaluation of 1, 7-naphthyridones as novel KDM5 inhibitors. Issue 18 (15th September 2016)

• Record Type: Journal Article
• Authors: Labadie, Sharada S.; Dragovich, Peter S.; Cummings, Richard T.; Deshmukh, Gauri; Gustafson, Amy; Han, Ning; Harmange, Jean-Christophe; Kiefer, James R.; Li, Yue; Liang, Jun; Liederer, Bianca M.; Liu, Yichin; Manieri, Wanda; Mao, Wiefeng; Murray, Lesley; Ortwine, Daniel F.; Trojer, Patrick; VanderPorten, Erica; Vinogradova, Maia; Wen, Li
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 18(2016)
• Page Start: 4492
• Page End: 4496
• Publication Date: 2016-09-15
• Subjects: Histone lysine demethylases -- KDM5 inhibitors -- Epigenetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.07.070
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1, 7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a representative molecule bound to KDM5A showed that these inhibitors are competitive with the co-substrate (2-oxoglutarate or 2-OG).