Gli transcription factors within the Hedgehog (Hh) signaling pathway direct key events in mammalian development and promote a number of human cancers. Current therapies for Gli‐driven tumors target Smoothened (SMO), a G protein‐coupled receptor‐like protein that functions upstream in the Hh pathway. Although these drugs can have remarkable clinical efficacy, mutations in SMO and downstream Hh pathway components frequently lead to chemoresistance. In principle, therapies that act at the level of Gli proteins, through direct or indirect mechanisms, would be more efficacious. We therefore screened 325 120 compounds for their ability to block the constitutive Gli activity induced by loss of Suppressor of Fused (SUFU), a scaffolding protein that directly inhibits Gli function. Our studies reveal a family of bicyclic imidazolium derivatives that can inhibit Gli‐dependent transcription without affecting the ciliary trafficking or proteolytic processing of these transcription factors. We anticipate that these chemical antagonists will be valuable tools for investigating the mechanisms of Gli regulation and developing new strategies for targeting Gli‐driven cancers.

中文翻译：

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Gli转录因子活性的双环咪唑鎓抑制剂。

刺猬（Hh）信号通路中的Gli转录因子指导哺乳动物发育中的关键事件并促进许多人类癌症。目前，针对Gli驱动的肿瘤的治疗方法以Smoothened（SMO）为目标，Smoothened（SMO）是一种G蛋白偶联受体样蛋白，在Hh通路的上游起作用。尽管这些药物可具有显着的临床疗效，但SMO和下游Hh途径组分的突变经常导致化学耐药性。原则上，通过直接或间接机制在Gli蛋白水平起作用的疗法将更为有效。因此，我们筛选了325120种化合物阻断由抑制融合蛋白（SUFU）（一种直接抑制Gli功能的支架蛋白）的丧失所诱导的组成性Gli活性的能力。我们的研究揭示了一个双环咪唑衍生物家族，它们可以抑制Gli依赖性转录，而不会影响这些转录因子的纤毛运输或蛋白水解过程。我们预计这些化学拮抗剂将成为研究Gli调节机制和开发针对Gli驱动的癌症的新策略的有价值的工具。