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
Posted on 2019-08-19 - 17:35
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. 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.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Collie, Gavin W.; Koh, Cheryl M.; O’Neill, Daniel J.; Stubbs, Christopher J.; Khurana, Puneet; Eddershaw, Alice; et al. (2019). Structural and Molecular Insight into Resistance Mechanisms
of First Generation cMET Inhibitors. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.9b00276
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
Read the peer-reviewed publication
AUTHORS (15)
GC
Gavin W. Collie
CK
Cheryl M. Koh
DO
Daniel J. O’Neill
CS
Christopher J. Stubbs
PK
Puneet Khurana
AE
Alice Eddershaw
AS
Arjan Snijder
FM
Fredrik Mauritzson
LB
Louise Barlind
ID
Ian L. Dale
JS
Joseph Shaw
CP
Christopher Phillips
EH
Edward J. Hennessy
TC
Tony Cheung
AN
Ana J. Narvaez