4XMO

Crystal structure of c-Met in complex with (R)-5-(8-fluoro-3-(1-fluoro-1-(3-methoxyquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methylisoxazole

Summary for 4XMO

• Entry DOI: 10.2210/pdb4xmo/pdb
• Descriptor: Hepatocyte growth factor receptor, 6-{(1R)-1-fluoro-1-[8-fluoro-6-(3-methyl-1,2-oxazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-methoxyquinoline (3 entities in total)
• Functional Keywords: receptor tyrosine kinase, intracellular catalytic domain, 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: 35637.11

Authors

Whittington, D.A.,Long, A.M. (deposition date: 2015-01-14, release date: 2015-03-11, Last modification date: 2024-02-28)

Primary citation

Peterson, E.A.,Teffera, Y.,Albrecht, B.K.,Bauer, D.,Bellon, S.F.,Boezio, A.,Boezio, C.,Broome, M.A.,Choquette, D.,Copeland, K.W.,Dussault, I.,Lewis, R.,Lin, M.H.,Lohman, J.,Liu, J.,Potashman, M.,Rex, K.,Shimanovich, R.,Whittington, D.A.,Vaida, K.R.,Harmange, J.C.
Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors.
J.Med.Chem., 58:2417-2430, 2015

PubMed Abstract: The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.

PubMed: 25699405
DOI: 10.1021/jm501913a

Experimental method

X-RAY DIFFRACTION (1.75 Å)