7B44

Crystal structure of c-MET bound by compound S1

Summary for 7B44

• Entry DOI: 10.2210/pdb7b44/pdb
• Descriptor: Hepatocyte growth factor receptor, 5-methoxy-1~{H}-indazole, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: c-met, kinase, folded p-loop, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34474.89

Authors

Collie, G.W. (deposition date: 2020-12-02, release date: 2020-12-09, Last modification date: 2024-05-01)

Primary citation

Collie, G.W.,Michaelides, I.N.,Embrey, K.,Stubbs, C.J.,Borjesson, U.,Dale, I.L.,Snijder, A.,Barlind, L.,Song, K.,Khurana, P.,Phillips, C.,Storer, R.I.
Structural Basis for Targeting the Folded P-Loop Conformation of c-MET.
Acs Med.Chem.Lett., 12:162-167, 2021

PubMed 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 () 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.

PubMed: 33488978
DOI: 10.1021/acsmedchemlett.0c00392

Experimental method

X-RAY DIFFRACTION (1.76 Å)