PDBsum entry 3ce3

Transferase

PDB id: 3ce3

Contents

Protein chain

293 a.a. *

Ligands

1FN

Waters ×65

* Residue conservation analysis

PDB id:

3ce3

Name:

Transferase

Title:

Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-met in complex with a pyrrolopyridinepyridone based inhibitor

Structure:

Hepatocyte growth factor receptor. Chain: a. Fragment: tyrosine kinase domain, unp residues 1049-1360. 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. Gene: met. Expressed in: spodoptera frugiperda. Expression_system_cell_line: spodoptera frugiperda 9 (sf9).

Resolution:

2.40Å R-factor: 0.210 R-free: 0.275

Authors:

J.Sack

Key ref:

K.S.Kim et al. (2008). Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities. J Med Chem, 51, 5330-5341. PubMed id: 18690676

Date:

28-Feb-08 Release date: 26-Aug-08

Protein chain

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

Seq: 1390 a.a.

Struc: 293 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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 51:5330-5341 (2008)

PubMed id: 18690676

Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.

K.S.Kim, L.Zhang, R.Schmidt, Z.W.Cai, D.Wei, D.K.Williams, L.J.Lombardo, G.L.Trainor, D.Xie, Y.Zhang, Y.An, J.S.Sack, J.S.Tokarski, C.Darienzo, A.Kamath, P.Marathe, Y.Zhang, J.Lippy, R.Jeyaseelan, B.Wautlet, B.Henley, J.Gullo-Brown, V.Manne, J.T.Hunt, J.Fargnoli, R.M.Borzilleri.

ABSTRACT

Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.