3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6

被引：46

作者：

Fraley, Mark E. ^{[1
]}

Steen, Justin T.

Brnardic, Edward J.

Arrington, Kenneth L.

Spencer, Keith L.

Hanney, Barbara A.

Kim, Yuntae

Hartman, George D.

Stirdivant, Steven M.

Drakas, Bob A.

Rickert, Keith

Walsh, Eileen S.

Hamilton, Kelly

Buser, Carolyn A.

Hardwick, James

Tao, Weikang

Beck, Stephen C.

Mao, Xianzhi

Lobell, Robert B.

Sepp-Lorenzino, Laura

Yan, Youwei

Ikuta, Mari

Munshi, Sanjeev K.

Kuo, Lawrence C.

Kreatsoulas, Constantine

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Biol Struct, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Mol Syst, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 23期

关键词：

Chek1; kinase; checkpoint escape; DNA damage; CDK7; oncology; indazoles; indoles;

D O I：

10.1016/j.bmcl.2006.08.118

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC50 = 0.30 nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：6049 / 6053

页数：5

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