PDBsum entry 5uad

Transferase/inhibitor

PDB id: 5uad

Contents

Protein chain

291 a.a.

Ligands

84P

Metals

_CL

Waters ×116

PDB id:

5uad

Name:

Transferase/inhibitor

Title:

Met tyrosine kinase inhibition enhances the antitumor efficacy of an hgf antibody

Structure:

Hepatocyte growth factor receptor. Chain: a. Fragment: unp residues 1041-1378. 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: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.25Å R-factor: 0.199 R-free: 0.252

Authors:

I.D.Hoffman,J.D.Lawson

Key ref:

P.J.Farrell et al. (2017). MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody. Mol Cancer Ther, 16, 1269-1278. PubMed id: 28341789 DOI: 10.1158/1535-7163.MCT-16-0771

Date:

19-Dec-16 Release date: 31-May-17

Protein chain

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

Seq: 1390 a.a.

Struc: 291 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

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: 10.1158/1535-7163.MCT-16-0771

Mol Cancer Ther 16:1269-1278 (2017)

PubMed id: 28341789

MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody.

P.J.Farrell, J.Matuszkiewicz, D.Balakrishna, S.Pandya, M.S.Hixon, R.Kamran, S.Chu, J.D.Lawson, K.Okada, A.Hori, A.Mizutani, H.Iwata, R.de Jong, B.Hibner, P.Vincent.

ABSTRACT

Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein.Mol Cancer Ther; 16(7); 1269-78. ©2017 AACR.