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

2010; American Chemical Society; Volume: 1; Issue: 3 Linguagem: Inglês

10.1021/ml1000307

1948-5875

Shifeng Pan, Xu Wu, Jiqing Jiang, Wenqi Gao, Yongqin Wan, Cheng Dai, Dong Han, Jun Liu, Nathan Englund, Yan Wang, Stefan Peukert, Karen Miller‐Moslin, Jing Yuan, Ribo Guo, Melissa Matsumoto, Anthony Vattay, Yun Jiang, Jeffrey Tsao, Fangxian Sun, AnneMarie Culazzo Pferdekamper, Stephanie Dodd, Tove Tuntland, Wieslawa Maniara, Joseph F. Kelleher, Yung‐Mae Yao, Markus Warmuth, Juliet Williams, Marion Dorsch,

Hedgehog Signaling Pathway Studies

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.