Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Labadie, Sharada S.¹  Dragovich, Peter S.¹  Cummings, Richard T.²  Deshmukh, Gauri¹  Gustafson, Amy¹  Han, Ning³  Harmange, Jean-Christophe²  Kiefer, James R.¹  Li, Yue³  Liang, Jun¹  Liederer, Bianca M.¹  Liu, Yichin¹  Manieri, Wanda²  Mao, Wiefeng³  Murray, Lesley¹  Ortwine, Daniel F.¹  Trojer, Patrick²  VanderPorten, Erica¹  Vinogradova, Maia¹  Wen, Li³ 

[1] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

[2] Constellat Pharmaceut Inc, 215 First St,Suite 200, Cambridge, MA 02142 USA

[3] Wuxi Apptec, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

关键词: Histone lysine demethylases;    KDM5 inhibitors;    Epigenetics;   

DOI  :  10.1016/j.bmcl.2016.07.070

来源: Elsevier

【 摘 要 】

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). (c) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

Free