Discovery of a selective c-MET inhibitor with a novel binding mode

Autor:	Gavin W. Collie, Louise Barlind, Sana Bazzaz, Ulf Börjesson, Ian L. Dale, Jeremy S. Disch, Sevan Habeshian, Rachael Jetson, Puneet Khurana, Andrew Madin, Iacovos N. Michaelides, Ling Peng, Arjan Snijder, Christopher J. Stubbs
Rok vydání:	2022
Předmět:	Small Molecule Libraries Cell Line Tumor Organic Chemistry Clinical Biochemistry Drug Discovery Pharmaceutical Science Molecular Medicine Antineoplastic Agents DNA Proto-Oncogene Proteins c-met Protein Kinase Inhibitors Molecular Biology Biochemistry
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 75:128948
ISSN:	0960-894X
Popis:	The c-MET receptor tyrosine kinase has received considerable attention as a cancer drug target yet there remains a need for inhibitors which are selective for c-MET and able to target emerging drug-resistant mutants. We report here the discovery, by screening a DNA-encoded chemical library, of a highly selective c-MET inhibitor which was shown by X-ray crystallography to bind to the kinase in an unprecedented manner. These results represent a novel mode of inhibiting c-MET with a small molecule and may provide a route to targeting drug-resistant forms of the kinase whilst avoiding potential toxicity issues associated with broad kinome inhibition.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2158b42d5205186ac58da0422919f965 https://doi.org/10.1016/j.bmcl.2022.128948 Zobrazit plný text záznamu Full Text from ScienceDirect