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Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors. 2018
Bernard Barlaam, and
Elaine Cadogan, and
Andrew Campbell, and
Nicola Colclough, and
Allan Dishington, and
Stephen Durant, and
Kristin Goldberg, and
Lorraine A Hassall, and
Gareth D Hughes, and
Philip A MacFaul, and
Thomas M McGuire, and
Martin Pass, and
Anil Patel, and
Stuart Pearson, and
Jens Petersen, and
Kurt G Pike, and
Graeme Robb, and
Natalie Stratton, and
Guohong Xin, and
Baochang Zhai
Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, U.K.
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 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.
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