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.
Shifeng Pan  1 ,  Xu Wu  1 ,  Jiqing Jiang  1 ,  Wenqi Gao  1 ,  Yongqin Wan  1 ,  Dai Cheng  1 ,  Dong Han  1 ,  Jun Liu  1 ,  Nathan P Englund  1 ,  Yan Wang  1 ,  Stefan Peukert  2 ,  Karen Miller-Moslin  2 ,  Jing Yuan  2 ,  Ribo Guo  2 ,  Melissa Matsumoto  2 ,  Anthony Vattay  2 ,  Yun Jiang  2 ,  Jeffrey Tsao  2 ,  Fangxian Sun  1 ,  AnneMarie C Pferdekamper  1 ,  Stephanie Dodd  2 ,  Tove Tuntland  1 ,  Wieslawa Maniara  2 ,  Joseph F Kelleher 3rd  2 ,  Yung-Mae Yao  2 ,  Markus Warmuth  2 ,  Juliet Williams  2 ,  Marion Dorsch  2
Affiliations
  • 1. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
  • 2. Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
PMID: 24900187 DOI: 10.1021/ml1000307
Abstract

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.
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