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