1. Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors
- Author
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Allan Dishington, Guohong Xin, Nicola Colclough, Stephen T. Durant, Anil Patel, Stuart E. Pearson, Lorraine A. Hassall, Kurt Gordon Pike, Kristin Goldberg, Thomas M. McGuire, Andrew D. Campbell, Baochang Zhai, Jens Petersen, Gareth Hughes, Elaine Cadogan, Barlaam Bernard Christophe, Natalie Stratton, Graeme R. Robb, Martin Pass, and Philip A. MacFaul
- Subjects
0301 basic medicine ,Kinase ,Organic Chemistry ,Cell ,Pharmacology ,Biochemistry ,Irinotecan ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Pharmacokinetics ,chemistry ,In vivo ,030220 oncology & carcinogenesis ,Drug Discovery ,medicine ,Potency ,IC50 ,Cinnoline ,medicine.drug - Abstract
[Image: see text] 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 IC(50) 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.
- Published
- 2018