Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

被引：44

作者：

Caldwell, John J. ^{[1
]}

Welsh, Emma J. ^{[1
]}

Matijssen, Cornelis ^{[1
]}

Anderson, Victoria E. ^{[1
]}

Antoni, Laurent ^{[1
]}

Boxall, Kathy ^{[1
]}

Urban, Frederique ^{[1
]}

Hayes, Angela ^{[1
]}

Raynaud, Florence I. ^{[1
]}

Rigoreau, Laurent J. M. ^{[3
]}

Raynham, Tony ^{[3
]}

Aherne, G. Wynne ^{[1
]}

Pearl, Laurence H. ^{[2
]}

Oliver, Antony W. ^{[2
]}

Garrett, Michelle D. ^{[1
]}

Collins, Ian ^{[1
]}

机构：

[1] Inst Canc Res, Canc Res UK Canc Therapeut Unit, Sutton SM2 5NG, Surrey, England

[2] Inst Canc Res, Sect Struct Biol, Chester Beatty Labs, London SW3 6JB, England

[3] Wolfson Inst Biomed Res, Canc Res Technol Discovery Labs London, London WC1E 6BT, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 02期

关键词：

CHK2; PROTEIN-KINASE; DNA-DAMAGE; IN-VITRO; CANCER; PHOSPHORYLATION; IDENTIFICATION; ASSAY; P53; AUTOPHOSPHORYLATION; OLIGOMERIZATION;

D O I：

10.1021/jm101150b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC50 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

引用

页码：580 / 590

页数：11

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