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Structural Basis for Targeting the Folded P-Loop Conformation of c-MET.

ABSTRACT: 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 (7) 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.

SUBMITTER: Collie GW

PROVIDER: S-EPMC7812667 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Structural Basis for Targeting the Folded P-Loop Conformation of c-MET.

Collie Gavin W GW Michaelides Iacovos N IN Embrey Kevin K Stubbs Christopher J CJ Börjesson Ulf U Dale Ian L IL Snijder Arjan A Barlind Louise L Song Kun K Khurana Puneet P Phillips Christopher C Storer R Ian RI

ACS medicinal chemistry letters 20201208 1

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 (<b>7</b>) 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 ...[more]

PMID: 33488978

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