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Structural and molecular insight into resistance mechanisms of first generation cMET inhibitors

DOI: 10.1021/acsmedchemlett.9b00276 DOI Help

Authors: Gavin W. Collie (AstraZeneca) , Cheryl M. Koh (AstraZeneca) , Daniel J. O'neill (AstraZeneca) , Christopher J. Stubbs (AstraZeneca) , Puneet Khurana (AstraZeneca) , Alice Eddershaw (AstraZeneca) , Arjan Snijder (AstraZeneca) , Fredrik Mauritzson (AstraZeneca) , Louise Barlind (AstraZeneca) , Ian L. Dale (AstraZeneca) , Joseph Shaw (AstraZeneca) , Christopher Phillips (AstraZeneca) , Edward J. Hennessy (AstraZeneca) , Tony Cheung (AstraZeneca) , Ana J. Narvaez (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 14631

Abstract: Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Towards this end we report here the first crystal structures of the recent clinically-observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase which could have implications for small molecule in-hibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.

Journal Keywords: cMET; kinase; drug resistance; small molecule inhibitor; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: SOLEIL