3B8Q

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

Summary for 3B8Q

• Entry DOI: 10.2210/pdb3b8q/pdb
• Related: 3B8R
• Descriptor: Vascular endothelial growth factor receptor 2, N-(4-chlorophenyl)-6-[(6,7-dimethoxyquinolin-4-yl)oxy]naphthalene-1-carboxamide (3 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: 73539.03

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

Harmange, J.C.,Weiss, M.M.,Germain, J.,Polverino, A.J.,Borg, G.,Bready, J.,Chen, D.,Choquette, D.,Coxon, A.,DeMelfi, T.,DiPietro, L.,Doerr, N.,Estrada, J.,Flynn, J.,Graceffa, R.F.,Harriman, S.P.,Kaufman, S.,La, D.S.,Long, A.,Martin, M.W.,Neervannan, S.,Patel, V.F.,Potashman, M.,Regal, K.,Roveto, P.M.,Schrag, M.L.,Starnes, C.,Tasker, A.,Teffera, Y.,Wang, L.,White, R.D.,Whittington, D.A.,Zanon, R.
Naphthamides as Novel and Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Design, Synthesis and Evaluation
J.Med.Chem., 51:1649-1667, 2008

PubMed 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.

PubMed: 18324761
DOI: 10.1021/jm701097z

Experimental method

X-RAY DIFFRACTION (2.75 Å)