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

ABSTRACT: 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 ?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.

SUBMITTER: Barlaam B

PROVIDER: S-EPMC6088353 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Barlaam Bernard B Cadogan Elaine E Campbell Andrew A Colclough Nicola N Dishington Allan A Durant Stephen S Goldberg Kristin K Hassall Lorraine A LA Hughes Gareth D GD MacFaul Philip A PA McGuire Thomas M TM Pass Martin M Patel Anil A Pearson Stuart S Petersen Jens J Pike Kurt G KG Robb Graeme G Stratton Natalie N Xin Guohong G Zhai Baochang B

ACS medicinal chemistry letters 20180713 8

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 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. In vivo, 21 ...[more]

PMID: 30128072

Dataset Information

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

Publications

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

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