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Collie, Gavin W; Michaelides, Iacovos N; Embrey, Kevin; Stubbs, Christopher J; Börjesson, Ulf; Dale, Ian L; Snijder, Arjan; Barlind, Louise; Song, Kun; Khurana, Puneet; Phillips, Christopher; Storer, R Ian
ACS medicinal chemistry letters, 01/2021, Letnik: 12, Številka: 1Journal Article
We report here a fragment screen directed toward the c-MET kinase from which we discovered a series of inhibitors able to bind to a rare conformation of the protein in which the P-loop adopts a collapsed, or folded, arrangement. Preliminary SAR exploration led to an inhibitor ( ) with nanomolar biochemical activity against c-MET and promising cell activity and kinase selectivity. These findings increase our structural understanding of the folded P-loop conformation of c-MET and provide a sound structural and chemical basis for further investigation of this underexplored yet potentially therapeutically exploitable conformational state.
