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. 2009 Oct 1;19(19):5576-81.
doi: 10.1016/j.bmcl.2009.08.049. Epub 2009 Aug 15.

GDC-0449-a potent inhibitor of the hedgehog pathway

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

GDC-0449-a potent inhibitor of the hedgehog pathway

Kirk D Robarge et al. Bioorg Med Chem Lett. .

Erratum in

  • Bioorg Med Chem Lett. 2010 Jan 15;20(2):771

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.

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