Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist
Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist
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DOI：
10.1021/ml1000307
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发表时间：
2010-06-01
影响因子：
4.2
通讯作者：
Dorsch, Marion
中科院分区：
文献类型：
--
作者：
Pan, Shifeng;Wu, Xu;Dorsch, Marion
异常刺猬（Hh）信号的阻断在癌症治疗干预中显示出了希望。进行了基于细胞的表型高通量筛选，并通过拮抗Smoothened受体（Smo）确定了导联结构(1)为Hh通路的抑制剂。构效关系研究发现了一种有效的特异性Smoothened拮抗剂N-(6-(2S,6R)-2,6-二甲基morpholino)pyridin-3-yl)- 2methyl - 1-4'-（三氟甲氧基）biphenyl-3-carboxamide (5m, nlp - lde225)，目前正处于临床开发阶段。
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-carboxamide (5m, NVP-LDE225), which is currently in clinical development.