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

被引：39

作者：

Nie, Zhe ^{[1
]}

Shi, Lihong ^{[1
]}

Lai, Chon ^{[1
]}

O'Connell, Shawn M. ^{[1
,3
]}

Xu, Jiangchun ^{[1
]}

Stansfield, Ryan K. ^{[1
,4
]}

Hosfield, David J. ^{[2
]}

Veal, James M. ^{[1
,4
]}

Stafford, Jeffrey A. ^{[1
,4
]}

机构：

[1] Celgene Corp, 10300 Campus Point Dr,Suite 100, San Diego, CA 92121 USA

[2] Univ Chicago, Ben May Dept Canc Res, 929 East 57th St, Chicago, IL 60637 USA

[3] Pfizer Inc, Groton, CT 06340 USA

[4] Jecure Therapeut, San Diego, CA USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 09期

关键词：

Epigenetics; Histone lysine demethylase; KDM5; Tri-methylated H3K4; Structure-based design; HISTONE DEMETHYLASES; CANCER; CELLS; MELANOMA; TARGETS;

D O I：

10.1016/j.bmcl.2018.03.083

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：1490 / 1494

页数：5

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