2. Academic Validation
  3. Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor

Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor

  • J Med Chem. 2007 Feb 22;50(4):611-26. doi: 10.1021/jm061107l.
Brian L Hodous 1,  Stephanie D Geuns-Meyer,  Paul E Hughes,  Brian K Albrecht,  Steve Bellon,  James Bready,  Sean Caenepeel,  Victor J Cee,  Stuart C Chaffee,  Angela Coxon,  Maurice Emery,  Jenne Fretland,  Paul Gallant,  Yan Gu,  Doug Hoffman,  Rebecca E Johnson,  Richard Kendall,  Joseph L Kim,  Alexander M Long,  Michael Morrison,  Philip R Olivieri,  Vinod F Patel,  Anthony Polverino,  Paul Rose,  Paul Tempest,  Ling Wang,  Douglas A Whittington,  Huilin Zhao
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139-1581, USA. bhodous@amgen.com
PMID: 17253678 DOI: 10.1021/jm061107l
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 VEGFR2/KDR/Flk-1 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.

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