Evolution of selective, potent, and orally bioavailable small molecule Tie-2 kinase inhibitors

MEDI 370

Philip R Olivieri II1, Stephanie D Geuns-Meyer1, Paul E Hughes2, Brian K Albrecht1, Steve Bellon3, James Bready2, Sean Caenepeel2, Victor J Cee1, Stuart C Chaffee1, Angela Coxon2, Maurice Emery4, Jenne Fretland4, Paul Gallant5, Yan Gu5, Brian L Hodous1, Doug Hoffman6, Rebecca E Johnson1, Richard Kendall2, Joseph L Kim3, Alexander M Long3, Michael Morrison5, Vinod F Patel1, Anthony Polverino2, Paul Rose5, Paul Tempest1, Ling Wang2, Douglas A Whittington3, and Huilin Zhao5. (1) Department of Medicinal Chemistry, Amgen, One Kendall Square, Building 1000, Cambridge, MA 02139, (2) Department of Oncology Research, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, (3) Department of Molecular Structure, Amgen, One Kendall Square, Building 1000, Cambridge, MA 02139, (4) Department of Pharmacokinetics and Drug Metabolism, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, (5) Department of Molecular Pharmacology, Amgen, One Kendall Square, Building 1000, Cambridge, MA 02139, (6) Department of Pharmaceutics, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed primarily in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. Interference with the Tie-2 pathway by diverse ligand/receptor blocking agents such as soluble Tie-2 receptors, antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in mouse xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves targeting the ATP-binding site of the Tie-2 kinase domain with small molecule inhibitors. Potent, orally bioavailable kinase inhibitors with selectivity over other kinases implicated in angiogenesis are required in order to properly evaluate the therapeutic utility of this approach. Towards this end, several selective DFG-out binding scaffolds evolved from a designed multi-kinase inhibitor with the aid of X-ray co-crystal structures of Tie-2 and KDR. These structurally diverse molecules demonstrated on-mechanism activity in in vivo models.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007