Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity

被引：180

作者：

Foote, Kevin M. ^{[1
]}

Blades, Kevin ^{[1
]}

Cronin, Anna ^{[1
]}

Fillery, Shaun ^{[1
]}

Guichard, Sylvie S. ^{[1
]}

Hassall, Lorraine ^{[1
]}

Hickson, Ian ^{[2
]}

Jacq, Xavier ^{[2
]}

Jewsbury, Philip J. ^{[1
]}

McGuire, Thomas M. ^{[1
]}

Nissink, J. Willem M. ^{[1
]}

Odedra, Rajesh ^{[1
]}

Page, Ken ^{[1
]}

Perkins, Paula ^{[1
]}

Suleman, Abid ^{[1
]}

Tam, Kin ^{[1
]}

Thommes, Pia ^{[1
]}

Broadhurst, Rebecca ^{[1
]}

Wood, Christine ^{[1
]}

机构：

[1] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England

[2] KuDOS Pharmaceut, Cambridge, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 05期

关键词：

CROSS-COUPLING REACTION; CYTOCHROME-P450; ENZYMES; CANCER-CELLS; DNA-DAMAGE; IDENTIFICATION; SENSITIVITY; RADIATION; CYCLE; REPLICATION; NVP-BEZ235;

D O I：

10.1021/jm301859s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.

引用

页码：2125 / 2138

页数：14

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