PDBsum entry 4eev

Transferase/transferase inhibitor

PDB id: 4eev

Contents

Protein chain

283 a.a.

Ligands

L1X

Waters ×125

PDB id:

4eev

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of c-met in complex with ly2801653

Structure:

Hepatocyte growth factor receptor. Chain: a. Fragment: kinase domain (unp residues 1038-1346). Synonym: hgf receptor, hgf/sf receptor, proto-oncogenE C-met, scatter factor receptor, sf receptor, tyrosine-protein kinase met. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: met. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.80Å R-factor: 0.190 R-free: 0.215

Authors:

Y.Wang,S.L.Stout

Key ref:

S.B.Yan et al. (2013). 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. PubMed id: 23275061 DOI: 10.1007/s10637-012-9912-9

Date:

28-Mar-12 Release date: 10-Apr-13

Protein chain

P08581  (MET_HUMAN) -  Hepatocyte growth factor receptor from Homo sapiens

Seq: 1390 a.a.

Struc: 283 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1007/s10637-012-9912-9

Invest New Drugs 31:833-844 (2013)

PubMed id: 23275061

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.

S.B.Yan, V.L.Peek, R.Ajamie, S.G.Buchanan, J.R.Graff, S.A.Heidler, Y.H.Hui, K.L.Huss, B.W.Konicek, J.R.Manro, C.Shih, J.A.Stewart, T.R.Stewart, S.L.Stout, M.T.Uhlik, S.L.Um, Y.Wang, W.Wu, L.Yan, W.J.Yang, B.Zhong, R.A.Walgren.

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).