8OV7

Crystal structure of D1228V c-MET bound by compound 10

Summary for 8OV7

• Entry DOI: 10.2210/pdb8ov7/pdb
• Descriptor: Hepatocyte growth factor receptor, 5-[3,5-bis(fluoranyl)phenyl]-1-[(1S)-1-[3-(1H-imidazol-5-yl)phenyl]ethyl]pyrimidine-2,4-dione (3 entities in total)
• Functional Keywords: kinase, inhibitor, cancer research, drug discovery, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35220.74

Authors

Collie, G.W. (deposition date: 2023-04-25, release date: 2023-07-05, Last modification date: 2024-06-19)

Primary citation

Michaelides, I.N.,Collie, G.W.,Borjesson, U.,Vasalou, C.,Alkhatib, O.,Barlind, L.,Cheung, T.,Dale, I.L.,Embrey, K.J.,Hennessy, E.J.,Khurana, P.,Koh, C.M.,Lamb, M.L.,Liu, J.,Moss, T.A.,O'Neill, D.J.,Phillips, C.,Shaw, J.,Snijder, A.,Storer, R.I.,Stubbs, C.J.,Han, F.,Li, C.,Qiao, J.,Sun, D.Q.,Wang, J.,Wang, P.,Yang, W.
Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor.
J.Med.Chem., 66:8782-8807, 2023

PubMed Abstract: Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.

PubMed: 37343272
DOI: 10.1021/acs.jmedchem.3c00401

Experimental method

X-RAY DIFFRACTION (1.95 Å)