GDC-0449-a potent inhibitor of the hedgehog pathway

  • Bioorg Med Chem Lett. 2009 Oct 1;19(19):5576-81. doi: 10.1016/j.bmcl.2009.08.049.
Kirk D Robarge  1 ,  Shirley A Brunton ,  Georgette M Castanedo ,  Yong Cui ,  Michael S Dina ,  Richard Goldsmith ,  Stephen E Gould ,  Oivin Guichert ,  Janet L Gunzner ,  Jason Halladay ,  Wei Jia ,  Cyrus Khojasteh ,  Michael F T Koehler ,  Karen Kotkow ,  Hank La ,  Rebecca L Lalonde ,  Kevin Lau ,  Leslie Lee ,  Derek Marshall ,  James C Marsters Jr ,  Lesley J Murray ,  Changgeng Qian ,  Lee L Rubin ,  Laurent Salphati ,  Mark S Stanley ,  John H A Stibbard ,  Daniel P Sutherlin ,  Savita Ubhayaker ,  Shumei Wang ,  Susan Wong ,  Minli Xie
Affiliations
  • 1. Genentech, Small Molecule Drug Discovery 1 DNA Way, South San Francisco, CA 94080, United States. [email protected]
PMID: 19716296 DOI: 10.1016/j.bmcl.2009.08.049
Abstract

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the Hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a Medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.