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[摘要]：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-dimethyl morpholino)pyridin-3-yl)-2methy1-4'-(trifluoromethoxy)biphenyl-3-carbox amide (5m, NVP-LDE225), which is currently in clinical development. |
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