3VW8

Crystal structure of human c-Met kinase domain with its inhibitor

Summary for 3VW8

• Entry DOI: 10.2210/pdb3vw8/pdb
• Descriptor: Hepatocyte growth factor receptor, N-({4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}carbamothioyl)-2-phenylacetamide, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: transferase, 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: 37593.85

Authors

Matsumoto, S.,Miyamoto, N.,Hirayama, T.,Oki, H.,Okada, K.,Tawada, M.,Iwata, H.,Miki, H.,Nakamura, K.,Hori, A.,Imamura, S. (deposition date: 2012-08-08, release date: 2013-08-14, Last modification date: 2024-05-29)

Primary citation

Matsumoto, S.,Miyamoto, N.,Hirayama, T.,Oki, H.,Okada, K.,Tawada, M.,Iwata, H.,Nakamura, K.,Yamasaki, S.,Miki, H.,Hori, A.,Imamura, S.
Structure-based design, synthesis, and evaluation of imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors.
Bioorg.Med.Chem., 21:7686-7698, 2013

PubMed Abstract: To identify compounds with potent antitumor efficacy for various human cancers, we aimed to synthesize compounds that could inhibit c-mesenchymal epithelial transition factor (c-Met) and vascular endothelial growth factor receptor 2 (VEGFR2) kinases. We designed para-substituted inhibitors by using co-crystal structural information from c-Met and VEGFR2 in complex with known inhibitors. This led to the identification of compounds 3a and 3b, which were capable of suppressing both c-Met and VEGFR2 kinase activities. Further optimization resulted in pyrazolone and pyridone derivatives, which could form intramolecular hydrogen bonds to enforce a rigid conformation, thereby producing potent inhibition. One compound of particular note was the imidazo[1,2-a]pyridine derivative (26) bearing a 6-methylpyridone ring, which strongly inhibited both c-Met and VEGFR2 enzyme activities (IC50=1.9, 2.2 nM), as well as proliferation of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein endothelial cells (IC50=5.0, 1.8 nM). Compound 26 exhibited dose-dependent antitumor efficacy in vivo in MKN45 (treated/control ratio [T/C]=4%, po, 5mg/kg, once-daily) and COLO205 (T/C=13%, po, 15 mg/kg, once-daily) mouse xenograft models.

PubMed: 24216091
DOI: 10.1016/j.bmc.2013.10.028

Experimental method

X-RAY DIFFRACTION (2.1 Å)