2RL5
Crystal structure of the VEGFR2 kinase domain in complex with a 2,3-dihydro-1,4-benzoxazine inhibitor
Summary for 2RL5
| Entry DOI | 10.2210/pdb2rl5/pdb |
| Descriptor | 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) |
| 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 |
| Total number of polymer chains | 1 |
| Total formula weight | 36776.51 |
| Authors | Whittington, D.A.,Long, A.M.,Rose, P.,Zhao, H. (deposition date: 2007-10-18, release date: 2008-04-08, Last modification date: 2024-10-16) |
| Primary citation | 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 Cited by 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: 18311900DOI: 10.1021/jm701129j PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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