ml9b00276_si_001.pdf (1.56 MB)
Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors
Version 2 2019-08-19, 17:35
Version 1 2019-08-17, 12:29
journal contribution
posted on 2019-08-19, 17:35 authored by Gavin W. Collie, Cheryl M. Koh, Daniel J. O’Neill, Christopher J. Stubbs, Puneet Khurana, Alice Eddershaw, Arjan Snijder, Fredrik Mauritzson, Louise Barlind, Ian L. Dale, Joseph Shaw, Christopher Phillips, Edward J. Hennessy, Tony Cheung, Ana J. NarvaezMany
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. Toward 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
inhibitor design. The data we report here increases our molecular
understanding of the D1228V cMET mutation and provides insight for
future inhibitor design.