PDBsum entry 5ew3

Transferase

PDB id: 5ew3

Contents

Protein chains

274 a.a.

Ligands

5T2 ×2

Waters ×76

PDB id:

5ew3

Name:

Transferase

Title:

Human vascular endothelial growth factor receptor 2 (kdr) kinase domain in complex with aal993

Structure:

Vascular endothelial growth factor receptor 2. Chain: a, b. Fragment: kinase domain, residues 806-1171. Synonym: vegfr-2,fetal liver kinase 1,flk-1,kinase insert domain receptor,kdr,protein-tyrosine kinase receptor flk-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kdr, flk1, vegfr2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.50Å R-factor: 0.219 R-free: 0.254

Authors:

W.Stark,A.Goepfert

Key ref:

G.Bold et al. (2016). A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis. J Med Chem, 59, 132-146. PubMed id: 26629594 DOI: 10.1021/acs.jmedchem.5b01582

Date:

20-Nov-15 Release date: 16-Dec-15

Protein chains

P35968  (VGFR2_HUMAN) -  Vascular endothelial growth factor receptor 2 from Homo sapiens

Seq: 1356 a.a.

Struc: 274 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

DOI no: 10.1021/acs.jmedchem.5b01582

J Med Chem 59:132-146 (2016)

PubMed id: 26629594

A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis.

G.Bold, C.Schnell, P.Furet, P.McSheehy, J.Brüggen, J.Mestan, P.W.Manley, P.Drückes, M.Burglin, U.Dürler, J.Loretan, R.Reuter, M.Wartmann, A.Theuer, B.Bauer-Probst, G.Martiny-Baron, P.Allegrini, A.Goepfert, J.Wood, A.Littlewood-Evans.

ABSTRACT

This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.