2QU5

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

Summary for 2QU5

• Entry DOI: 10.2210/pdb2qu5/pdb
• Related: 2QU6
• Descriptor: Vascular endothelial growth factor receptor 2, 4-[[2-[[4-chloro-3-(trifluoromethyl)phenyl]amino]-3H-benzimidazol-5-yl]oxy]-N-methyl-pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: receptor tyrosinse kinase, kdr, 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: 1
• Total formula weight: 36746.41

Authors

Whittington, D.A.,Kim, J.L.,Long, A.M.,Rose, P.,Gu, Y.,Zhao, H. (deposition date: 2007-08-03, release date: 2007-09-25, Last modification date: 2024-10-30)

Primary citation

Potashman, M.H.,Bready, J.,Coxon, A.,Demelfi, T.M.,Dipietro, L.,Doerr, N.,Elbaum, D.,Estrada, J.,Gallant, P.,Germain, J.,Gu, Y.,Harmange, J.C.,Kaufman, S.A.,Kendall, R.,Kim, J.L.,Kumar, G.N.,Long, A.M.,Neervannan, S.,Patel, V.F.,Polverino, A.,Rose, P.,Plas, S.V.,Whittington, D.,Zanon, R.,Zhao, H.
Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors.
J.Med.Chem., 50:4351-4373, 2007

PubMed Abstract: Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).

PubMed: 17696416
DOI: 10.1021/jm070034i

Experimental method

X-RAY DIFFRACTION (2.95 Å)