PDBsum entry 3efk

Transferase

PDB id: 3efk

Contents

Protein chains

276 a.a. *

Ligands

MT4 ×2

Waters ×111

* Residue conservation analysis

PDB id:

3efk

Name:

Transferase

Title:

Structure of c-met with pyrimidone inhibitor 50

Structure:

Hepatocyte growth factor receptor. Chain: a, b. Fragment: c-met kinase domain, unp residues 1048-1351. Synonym: hgf receptor, scatter factor receptor, sf receptor, hgf/sf receptor, met proto-oncogene tyrosine kinase, c-met. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: met. Expressed in: spodoptera frugiperda

Resolution:

2.20Å R-factor: 0.257 R-free: 0.292

Authors:

S.F.Bellon,N.D'Angelo,D.Whittington,I.Dussault

Key ref:

N.D.D'Angelo et al. (2008). Design, synthesis, and biological evaluation of potent c-Met inhibitors. J Med Chem, 51, 5766-5779. PubMed id: 18763753

Date:

09-Sep-08 Release date: 07-Oct-08

Protein chains

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

Seq: 1390 a.a.

Struc: 276 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

J Med Chem 51:5766-5779 (2008)

PubMed id: 18763753

Design, synthesis, and biological evaluation of potent c-Met inhibitors.

N.D.D'Angelo, S.F.Bellon, S.K.Booker, Y.Cheng, A.Coxon, C.Dominguez, I.Fellows, D.Hoffman, R.Hungate, P.Kaplan-Lefko, M.R.Lee, C.Li, L.Liu, E.Rainbeau, P.J.Reider, K.Rex, A.Siegmund, Y.Sun, A.S.Tasker, N.Xi, S.Xu, Y.Yang, Y.Zhang, T.L.Burgess, I.Dussault, T.S.Kim.

ABSTRACT

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.