2P4I

Evolution of a highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor

2P4I の概要

• エントリーDOI: 10.2210/pdb2p4i/pdb
• 関連するPDBエントリー: 2oo8
• 分子名称: Angiopoietin-1 receptor, 4-METHYL-3-({3-[2-(METHYLAMINO)PYRIMIDIN-4-YL]PYRIDIN-2-YL}OXY)-N-[2-MORPHOLIN-4-YL-5-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE (3 entities in total)
• 機能のキーワード: tie-2 kinase inhibitor triazine, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: Q02763
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 73635.77

構造登録者

Bellon, S.F. (登録日: 2007-03-12, 公開日: 2007-03-20, 最終更新日: 2024-02-21)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.5 Å)