Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors

被引：24

作者：

Barlaam, Bernard ^{[1
]}

Cadogan, Elaine ^{[1
]}

Campbell, Andrew ^{[2
]}

Colclough, Nicola ^{[1
]}

Dishington, Allan ^{[2
]}

Durant, Stephen ^{[1
]}

Goldberg, Kristin ^{[1
]}

Hassall, Lorraine A. ^{[2
]}

Hughes, Gareth D. ^{[1
]}

MacFaul, Philip A. ^{[2
]}

McGuire, Thomas M. ^{[1
]}

Pass, Martin ^{[1
]}

Patel, Anil ^{[2
]}

Pearson, Stuart ^{[1
]}

Petersen, Jens ^{[3
]}

Pike, Kurt G. ^{[1
]}

Robb, Graeme ^{[1
]}

Stratton, Natalie ^{[4
]}

Xin, Guohong ^{[5
]}

Zhai, Baochang ^{[5
]}

机构：

[1] AstraZeneca, Oncol, IMED Biotech Unit, Cambridge, England

[2] AstraZeneca, Oncol, IMED Biotech Unit, Macclesfield, Cheshire, England

[3] AstraZeneca, Discovery Sci, IMED Biotech Unit, Gothenburg, Sweden

[4] AstraZeneca, Discovery Sci, IMED Biotech Unit, Cambridge, England

[5] Pharmaron Beijing Co Ltd, 6 Taihe Rd BDA, Beijing, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 08期

关键词：

ATM; ataxia telangiectasia mutated kinase; PIKK; DDR; OXIDATIVE STRESS; ACTIVATION; KINASE;

D O I：

10.1021/acsmedchemlett.8b00200

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound 21, a highly potent ATM inhibitor (ATM cell IC50 0.0028 mu M) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. In vivo, 21 in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound 21 was selected for preclinical evaluation alongside AZD0156.

引用

页码：809 / 814

页数：11

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