5EYC

Crystal structure of c-Met in complex with naphthyridinone inhibitor 5

Summary for 5EYC

• Entry DOI: 10.2210/pdb5eyc/pdb
• Related: 5EYD
• Descriptor: Hepatocyte growth factor receptor, 6-[(1~{R})-1-[8-fluoranyl-6-(3-methyl-1,2-oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl]-1,6-naphthyridin-5-one (3 entities in total)
• Functional Keywords: phosphotransferase, inhibitor, cancer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• Total number of polymer chains: 1
• Total formula weight: 35606.09

Authors

Whittington, D.A.,Long, A.M. (deposition date: 2015-11-24, release date: 2016-02-10, Last modification date: 2023-09-27)

Primary citation

Boezio, A.A.,Copeland, K.W.,Rex, K.,K Albrecht, B.,Bauer, D.,Bellon, S.F.,Boezio, C.,Broome, M.A.,Choquette, D.,Coxon, A.,Dussault, I.,Hirai, S.,Lewis, R.,Lin, M.H.,Lohman, J.,Liu, J.,Peterson, E.A.,Potashman, M.,Shimanovich, R.,Teffera, Y.,Whittington, D.A.,Vaida, K.R.,Harmange, J.C.
Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.
J.Med.Chem., 59:2328-2342, 2016

PubMed Abstract: Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.

PubMed: 26812066
DOI: 10.1021/acs.jmedchem.5b01716

Experimental method

X-RAY DIFFRACTION (1.8 Å)