PDBsum entry 3b8q

Transferase

PDB id: 3b8q

Contents

Protein chains

292 a.a. *

271 a.a. *

Ligands

900 ×2

Waters ×65

* Residue conservation analysis

PDB id:

3b8q

Name:

Transferase

Title:

Crystal structure of the vegfr2 kinase domain in complex with a naphthamide inhibitor

Structure:

Vascular endothelial growth factor receptor 2. Chain: a, b. Fragment: kinase domain. Unp residues 815-939, 990-1171. Synonym: vegfr-2, kinase insert domain receptor, protein-tyrosine kinase receptor flk-1, cd309 antigen. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kdr, flk1. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.

Resolution:

2.75Å R-factor: 0.218 R-free: 0.276

Authors:

D.A.Whittington,A.M.Long,Y.Gu,H.Zhao

Key ref:

J.C.Harmange et al. (2008). Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation. J Med Chem, 51, 1649-1667. PubMed id: 18324761

Date:

01-Nov-07 Release date: 01-Apr-08

Protein chain

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

Seq: 1356 a.a.

Struc: 292 a.a.*

Protein chain

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

Seq: 1356 a.a.

Struc: 271 a.a.*

* PDB and UniProt seqs differ at 10 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: 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 51:1649-1667 (2008)

PubMed id: 18324761

Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation.

J.C.Harmange, M.M.Weiss, J.Germain, A.J.Polverino, G.Borg, J.Bready, D.Chen, D.Choquette, A.Coxon, T.DeMelfi, L.DiPietro, N.Doerr, J.Estrada, J.Flynn, R.F.Graceffa, S.P.Harriman, S.Kaufman, D.S.La, A.Long, M.W.Martin, S.Neervannan, V.F.Patel, M.Potashman, K.Regal, P.M.Roveto, M.L.Schrag, C.Starnes, A.Tasker, Y.Teffera, L.Wang, R.D.White, D.A.Whittington, R.Zanon.

ABSTRACT

A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.