Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist

ACS Med Chem Lett. 2010 Mar 16;1(3):130-4. doi: 10.1021/ml1000307. eCollection 2010 Jun 10.


The blockade of aberrant hedgehog (Hh) signaling has shown promise for therapeutic intervention in cancer. A cell-based phenotypic high-throughput screen was performed, and the lead structure (1) was identified as an inhibitor of the Hh pathway via antagonism of the Smoothened receptor (Smo). Structure-activity relationship studies led to the discovery of a potent and specific Smoothened antagonist N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)biphenyl-3-carboxamide (5m, NVP-LDE225), which is currently in clinical development.

Keywords: Hedgehog signaling pathway; Smoothened; medulloblastoma.