4EEV

Crystal structure of c-Met in complex with LY2801653

Summary for 4EEV

• Entry DOI: 10.2210/pdb4eev/pdb
• Descriptor: Hepatocyte growth factor receptor, N-(3-fluoro-4-{[1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (3 entities in total)
• Functional Keywords: protein tyrosine kinase, 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: 36486.11

Authors

Wang, Y.,Stout, S.L. (deposition date: 2012-03-28, release date: 2013-04-10, Last modification date: 2024-02-28)

Primary citation

Yan, S.B.,Peek, V.L.,Ajamie, R.,Buchanan, S.G.,Graff, J.R.,Heidler, S.A.,Hui, Y.H.,Huss, K.L.,Konicek, B.W.,Manro, J.R.,Shih, C.,Stewart, J.A.,Stewart, T.R.,Stout, S.L.,Uhlik, M.T.,Um, S.L.,Wang, Y.,Wu, W.,Yan, L.,Yang, W.J.,Zhong, B.,Walgren, R.A.
LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.
Invest New Drugs, 31:833-844, 2013

PubMed Abstract: The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia, including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome. We report here preclinical development of a potent, orally bioavailable, small-molecule inhibitor LY2801653 targeting MET kinase. LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM, a pharmacodynamic residence time (Koff) of 0.00132 min(-1) and t1/2 of 525 min. LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies (such as colon, bile ducts, and lung) is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037).

PubMed: 23275061
DOI: 10.1007/s10637-012-9912-9

Experimental method

X-RAY DIFFRACTION (1.8 Å)