5EW3

Human Vascular Endothelial Growth Factor Receptor 2 (KDR) Kinase Domain in complex with AAL993

Summary for 5EW3

• Entry DOI: 10.2210/pdb5ew3/pdb
• Descriptor: Vascular endothelial growth factor receptor 2, 2-(pyridin-4-ylmethylamino)-~{N}-[3-(trifluoromethyl)phenyl]benzamide (3 entities in total)
• Functional Keywords: kdr, kinase domain, atp-binding site, vegfr2 inhibitors, transferase
• Biological source: Homo sapiens (Human)
• 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: 73132.24

Authors

Stark, W.,Goepfert, A. (deposition date: 2015-11-20, release date: 2015-12-16, Last modification date: 2024-01-10)

Primary citation

Bold, G.,Schnell, C.,Furet, P.,McSheehy, P.,Bruggen, J.,Mestan, J.,Manley, P.W.,Druckes, P.,Burglin, M.,Durler, U.,Loretan, J.,Reuter, R.,Wartmann, M.,Theuer, A.,Bauer-Probst, B.,Martiny-Baron, G.,Allegrini, P.,Goepfert, A.,Wood, J.,Littlewood-Evans, A.
A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis.
J.Med.Chem., 59:132-146, 2016

PubMed Abstract: This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

PubMed: 26629594
DOI: 10.1021/acs.jmedchem.5b01582

Experimental method

X-RAY DIFFRACTION (2.5 Å)