2RL5

Crystal structure of the VEGFR2 kinase domain in complex with a 2,3-dihydro-1,4-benzoxazine inhibitor

2RL5 の概要

• エントリーDOI: 10.2210/pdb2rl5/pdb
• 分子名称: Vascular endothelial growth factor receptor 2, N-(4-CHLOROPHENYL)-7-[(6,7-DIMETHOXYQUINOLIN-4-YL)OXY]-2,3-DIHYDRO-1,4-BENZOXAZINE-4-CARBOXAMIDE (3 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36776.51

構造登録者

Whittington, D.A.,Long, A.M.,Rose, P.,Zhao, H. (登録日: 2007-10-18, 公開日: 2008-04-08, 最終更新日: 2024-10-16)

主引用文献

La, D.S.,Belzile, J.,Bready, J.V.,Coxon, A.,Demelfi, T.,Doerr, N.,Estrada, J.,Flynn, J.C.,Flynn, S.R.,Graceffa, R.F.,Harriman, S.P.,Larrow, J.F.,Long, A.M.,Martin, M.W.,Morrison, M.J.,Patel, V.F.,Roveto, P.M.,Wang, L.,Weiss, M.M.,Whittington, D.A.,Teffera, Y.,Zhao, Z.,Polverino, A.J.,Harmange, J.C.
Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis.
J.Med.Chem., 51:1695-1705, 2008

PubMed Abstract: Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.

PubMed: 18311900
DOI: 10.1021/jm701129j

実験手法

X-RAY DIFFRACTION (2.65 Å)