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

被引：16

作者：

Labadie, Sharada S. ^{[1
]}

Dragovich, Peter S. ^{[1
]}

Cummings, Richard T. ^{[2
]}

Deshmukh, Gauri ^{[1
]}

Gustafson, Amy ^{[1
]}

Han, Ning ^{[3
]}

Harmange, Jean-Christophe ^{[2
]}

Kiefer, James R. ^{[1
]}

Li, Yue ^{[3
]}

Liang, Jun ^{[1
]}

Liederer, Bianca M. ^{[1
]}

Liu, Yichin ^{[1
]}

Manieri, Wanda ^{[2
]}

Mao, Wiefeng ^{[3
]}

Murray, Lesley ^{[1
]}

Ortwine, Daniel F. ^{[1
]}

Trojer, Patrick ^{[2
]}

VanderPorten, Erica ^{[1
]}

Vinogradova, Maia ^{[1
]}

Wen, Li ^{[3
]}

机构：

[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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 18期

基金：

美国国家卫生研究院;

关键词：

Histone lysine demethylases; KDM5; inhibitors; Epigenetics; LYSINE DEMETHYLASE INHIBITORS; HISTONE DEMETHYLASES; CANCER-CELLS; DRUG DISCOVERY; TARGETS; FAMILY; IDENTIFICATION; DERIVATIVES; SURVIVAL; POTENT;

D O I：

10.1016/j.bmcl.2016.07.070

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：4492 / 4496

页数：5

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