2QU6

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

2QU6 の概要

• エントリーDOI: 10.2210/pdb2qu6/pdb
• 関連するPDBエントリー: 2QU5
• 分子名称: Vascular endothelial growth factor receptor 2, SULFATE ION, 4-({2-[(4-chloro-3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}phenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide, ... (4 entities in total)
• 機能のキーワード: receptor tyrosine kinase, kdr, angiogenesis, atp-binding, developmental protein, differentiation, glycoprotein, host-virus interaction, immunoglobulin domain, membrane, nucleotide-binding, phosphorylation, polymorphism, transferase, transmembrane, tyrosine-protein kinase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell junction . Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted . Isoform 3: Secreted: P35968
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 73681.17

構造登録者

Whittington, D.A.,Kim, J.L.,Long, A.M.,Rose, P.,Gu, Y.,Zhao, H. (登録日: 2007-08-03, 公開日: 2007-09-25, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)