Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor.

Autor:	Michaelides IN; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Collie GW; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Börjesson U; Discovery Sciences, R&D, AstraZeneca, 43183 Mölndal, Sweden., Vasalou C; DMPK, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States., Alkhatib O; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Barlind L; Discovery Sciences, R&D, AstraZeneca, 43183 Mölndal, Sweden., Cheung T; Bioscience, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States., Dale IL; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Embrey KJ; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Hennessy EJ; Medicinal Chemistry, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States., Khurana P; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Koh CM; Bioscience, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States., Lamb ML; Computational Chemistry, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States., Liu J; Discovery Sciences, R&D, AstraZeneca, 43183 Mölndal, Sweden., Moss TA; Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, United Kingdom., O'Neill DJ; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Phillips C; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Shaw J; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Snijder A; Discovery Sciences, R&D, AstraZeneca, 43183 Mölndal, Sweden., Storer RI; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Stubbs CJ; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom., Han F; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176 Beijing, People's Republic of China., Li C; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176 Beijing, People's Republic of China., Qiao J; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176 Beijing, People's Republic of China., Sun DQ; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176 Beijing, People's Republic of China., Wang J; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176 Beijing, People's Republic of China., Wang P; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176 Beijing, People's Republic of China., Yang W; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176 Beijing, People's Republic of China.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Jul 13; Vol. 66 (13), pp. 8782-8807. Date of Electronic Publication: 2023 Jun 21.
DOI:	10.1021/acs.jmedchem.3c00401
Abstrakt:	Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand 2 was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat in vivo studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.
Databáze:	MEDLINE
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