Identification of a potent antagonist of smoothened in hedgehog signaling.
Identification of a potent antagonist of smoothened in hedgehog signaling.
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Hedgehog 信号传导中 smoothened 的有效拮抗剂的鉴定
DOI：
10.1186/s13578-021-00558-9
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发表时间：
2021-03-02
影响因子：
7.5
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Fan J;Li H;Kuang L;Zhao Z;He W;Liu C;Wang Y;Cheng SY;Chen W
刺猬信号对于胚胎发育、组织稳态和干细胞自我更新的调控至关重要，使其成为开发癌症治疗的主要靶点。鉴于异常Hedgehog信号与癌症之间的密切联系，许多小分子化合物被开发出来抑制Smoothened（该通路的关键信号传感器）用于治疗癌症，并且一些这样的化合物已被美国食品和药物管理局批准（GDC-0449和LDE-225）。然而，获得性耐药已成为有效使用这些第一代Hedgehog途径阻滞剂的重要障碍。因此，新的平滑抑制剂可以克服这种阻力是迫切需要向前发展。结果在发现Hedgehog信号通路机制的基础上，我们建立了Smoothened/βarrestin2-GFP高通量筛选平台，并发现了0025A等多个靶向Smoothened的活性小分子。本研究表明，0025A可以阻断βarrestin2-GFP向Smoothened的移位，取代bodippy - cycloparamine与野生型Smoothened或突变型Smoothened- d473h的结合，减少Smo在初级纤毛上的积累和Hedgehog刺激下Gli的表达。此外，我们发现0025A可以有效抑制小鼠毛囊形态发生和毛发生长。结论0025A是一种有效的靶向Hedgehog信号通路中Smoothened野生型和突变型受体的拮抗剂，可能为难治性癌症提供新的治疗方法。
BackgroundHedgehog signaling is essential to the regulation of embryonic development, tissue homeostasis, and stem cell self-renewal, making it a prime target for developing cancer therapeutics. Given the close link between aberrant Hedgehog signaling and cancers, many small molecular compounds have been developed to inhibit Smoothened, a key signal transducer of this pathway, for treating cancer and several such compounds have been approved by the United States Food and Drug Administration (GDC-0449 and LDE-225). However, acquired drug resistance has emerged as an important obstacle to the effective use of these first generation Hedgehog pathway blockers. Thus, new Smoothened inhibitors that can overcome such resistance is an urgent need going forward.ResultsWe established the Smoothened/βarrestin2-GFP high-throughput screening platform based on the mechanistic discovery of Hedgehog signaling pathway, and discovered several active small molecules targeting Smoothened including 0025A. Here we show that 0025A can block the translocation of βarrestin2-GFP to Smoothened, displace Bodipy-cyclopamine binding to wild-type Smoothened or mutant Smoothened-D473H, reduce the accumulation of Smo on primary cilia and the expression of Gli upon Hedgehog stimulation. In addition, we show that 0025A can effectively suppress hair follicle morphogenesis and hair growth in mice.ConclusionsOur results demonstrate that 0025A is a potent antagonist targeting Smoothened wild-type and mutant receptors in the Hedgehog signaling pathway and may provide a new therapy for refractory cancers.
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影响因子：
13.8
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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通讯作者：
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作者：
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刺猬信号转导：主要参与者，致癌驱动因素和癌症治疗。
影响因子：
11.8
作者：
Pak, Ekaterina;Segal, Rosalind A.
通讯作者：
Segal, Rosalind A.