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
Bioorg. Med. Chem. Lett., 2022, 128948
https://doi.org/10.1016/j.bmcl.2022.128948

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.