2. Academic Validation
  3. Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist

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

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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