2P2I

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

Summary for 2P2I

• Entry DOI: 10.2210/pdb2p2i/pdb
• Related: 2P2H
• Descriptor: Vascular endothelial growth factor receptor 2, N-(4-phenoxyphenyl)-2-[(pyridin-4-ylmethyl)amino]nicotinamide (3 entities in total)
• Functional Keywords: receptor tyrosine kinase, kdr, transferase
• 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: 2
• Total formula weight: 73358.11

Authors

Whittington, D.A.,Kim, J.L.,Long, A.M.,Rose, P.,Gu, Y.,Zhao, H. (deposition date: 2007-03-07, release date: 2007-03-20, Last modification date: 2024-11-13)

Primary citation

Hodous, B.L.,Geuns-Meyer, S.D.,Hughes, P.E.,Albrecht, B.K.,Bellon, S.,Bready, J.,Caenepeel, S.,Cee, V.J.,Chaffee, S.C.,Coxon, A.,Emery, M.,Fretland, J.,Gallant, P.,Gu, Y.,Hoffman, D.,Johnson, R.E.,Kendall, R.,Kim, J.L.,Long, A.M.,Morrison, M.,Olivieri, P.R.,Patel, V.F.,Polverino, A.,Rose, P.,Tempest, P.,Wang, L.,Whittington, D.A.,Zhao, H.
Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor
J.Med.Chem., 50:611-626, 2007

PubMed Abstract: Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.

PubMed: 17253678
DOI: 10.1021/jm061107l

Experimental method

X-RAY DIFFRACTION (2.4 Å)