Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade
Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade
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DOI：
10.1073/pnas.0907134106
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发表时间：
2009-08-18
影响因子：
11.1
通讯作者：
Chen, James K.
中科院分区：
文献类型：
--
作者：
Hyman, Joel M.;Firestone, Ari J.;Chen, James K.
Hedgehog（Hh）信号通路的不适当激活与多种癌症有关，其药理学阻断已成为一种抗肿瘤策略。虽然几乎所有已知的Hh通路拮抗剂都靶向跨膜蛋白Smoothened（Smo），但抑制下游效应子的小分子可以更全面地修复Hh通路依赖性肿瘤。我们在这里报告了四种Hh通路拮抗剂，它们对核质调节因子Suppressor of Fused [Su（fu）]具有上位性，其中两种可以抑制Gli转录因子过表达诱导的Hh靶基因表达。每种抑制剂都有独特的作用机制，它们的表型表明Gli加工、Gli激活和初级纤毛形成是可靶向的。我们进一步建立了某些化合物阻断表达Smo致癌形式的小脑颗粒神经元前体细胞增殖的能力，并且我们证明了Hh通路抑制剂可以具有组织特异性活性。因此，这些拮抗剂构成了一组有价值的化学工具，用于询问下游Hh信号传导机制和开发针对Hh通路相关癌症的化学疗法。
Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum of cancers, and its pharmacological blockade has emerged as an anti-tumor strategy. While nearly all known Hh pathway antagonists target the transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more comprehensively remediate Hh pathway-dependent tumors. We report here four Hh pathway antagonists that are epistatic to the nucleocytoplasmic regulator Suppressor of Fused [Su(fu)], including two that can inhibit Hh target gene expression induced by overexpression of the Gli transcription factors. Each inhibitor has a unique mechanism of action, and their phenotypes reveal that Gli processing, Gli activation, and primary cilia formation are pharmacologically targetable. We further establish the ability of certain compounds to block the proliferation of cerebellar granule neuron precursors expressing an oncogenic form of Smo, and we demonstrate that Hh pathway inhibitors can have tissue-specific activities. These antagonists therefore constitute a valuable set of chemical tools for interrogating downstream Hh signaling mechanisms and for developing chemotherapies against Hh pathway-related cancers.