The hedgehog (Hh) signaling pathway is involved in diverse aspects of cellular events. Aberrant activation of Hh signaling pathway drives oncogenic transformation for a wide range of cancers, and it is therefore a promising target in cancer therapy. In the principle of association and ring‐opening, we designed and synthesized a series of Hh signaling pathway inhibitors with phenyl imidazole scaffold, which were biologically evaluated in Gli‐Luc reporter assay. Compound 25 was identified to possess high potency with nanomolar IC₅₀, and moreover, it preserved the inhibition against wild‐type and drug‐resistant Smo‐overexpressing cells. A molecular modeling study of compound 25 expounded its binding mode to Smo receptor, providing a basis for the further structural modification of phenyl imidazole analogs.

中文翻译：

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苯基咪唑类似物作为刺猬信号通路抑制剂的设计和生物学评价

刺猬 (Hh) 信号通路参与细胞事件的各个方面。Hh 信号通路的异常激活驱动了多种癌症的致癌转化，因此它是癌症治疗的一个有希望的目标。本着缔合和开环原理，我们设计合成了一系列具有苯基咪唑支架的Hh信号通路抑制剂，并在Gli-Luc报告基因检测中进行了生物学评估。化合物25被鉴定为具有纳摩尔 IC _{50 的}高效能，此外，它保留了对野生型和耐药性 Smo 过表达细胞的抑制作用。化合物25的分子模型研究 阐述了其与Smo受体的结合方式，为苯基咪唑类似物的进一步结构修饰提供了基础。