3B8R

Crystal structure of the VEGFR2 kinase domain in complex with a naphthamide inhibitor

Summary for 3B8R

• Entry DOI: 10.2210/pdb3b8r/pdb
• Related: 3B8Q
• Descriptor: Vascular endothelial growth factor receptor 2, 1,2-ETHANEDIOL, N-cyclopropyl-6-[(6,7-dimethoxyquinolin-4-yl)oxy]naphthalene-1-carboxamide, ... (4 entities in total)
• Functional Keywords: receptor tyrosine kinase, angiogenesis, atp-binding, developmental protein, differentiation, glycoprotein, host-virus interaction, immunoglobulin domain, membrane, nucleotide-binding, phosphorylation, polymorphism, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (human); More
• Cellular location: Cell junction . Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted . Isoform 3: Secreted: P35968
• Total number of polymer chains: 2
• Total formula weight: 73460.15

Authors

Whittington, D.A.,Long, A.M.,Gu, Y.,Zhao, H. (deposition date: 2007-11-01, release date: 2008-04-01, Last modification date: 2024-10-30)

Primary citation

Weiss, M.M.,Harmange, J.C.,Polverino, A.J.,Bauer, D.,Berry, L.,Berry, V.,Borg, G.,Bready, J.,Chen, D.,Choquette, D.,Coxon, A.,DeMelfi, T.,Doerr, N.,Estrada, J.,Flynn, J.,Graceffa, R.F.,Harriman, S.P.,Kaufman, S.,La, D.S.,Long, A.,Neervannan, S.,Patel, V.F.,Potashman, M.,Regal, K.,Roveto, P.M.,Schrag, M.L.,Starnes, C.,Tasker, A.,Teffera, Y.,Whittington, D.A.,Zanon, R.
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, 2008

PubMed 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.

PubMed: 18324759
DOI: 10.1021/jm701098w

Experimental method

X-RAY DIFFRACTION (2.7 Å)