PDBsum entry 3b8r

Transferase

PDB id: 3b8r

Contents

Protein chains

289 a.a. *

267 a.a. *

Ligands

EDO

887 ×2

Waters ×112

* Residue conservation analysis

PDB id:

3b8r

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:

2.70Å R-factor: 0.204 R-free: 0.259

Authors:

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

Key ref:

M.M.Weiss et al. (2008). Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors. J Med Chem, 51, 1668-1680. PubMed id: 18324759

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: 289 a.a.*

Protein chain

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

Seq: 1356 a.a.

Struc: 267 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 51:1668-1680 (2008)

PubMed id: 18324759

Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.

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

ABSTRACT

We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.