Sun Chiyu, Zhang Dajun, Luan Tian, Wang Youbing, Zhang Wenhu, Lin Lin, Jiang Meihua, Hao Ziqian, Wang Ying
School of Pharmacy, Shenyang Medical College Shenyang 110034 China
RSC Adv. 2021 Jun 28;11(37):22820-22825. doi: 10.1039/d1ra00732g. eCollection 2021 Jun 25.
Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We report herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway inhibition with a nanomolar IC value, and it prevented Shh-induced Smo from entering the primary cilium. Furthermore, mutant Smo was effectively suppressed compound 21. The antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results.
异常的刺猬信号通路（Hh）与多种癌症的发生发展有关。平滑蛋白（Smo）是Hh信号转导的一个瓶颈。靶向Smo受体调控Hh信号通路是开发抗癌药物的一种可行方法。我们在此报告了一系列2-甲氧基苯甲酰胺衍生物作为Hh信号通路抑制剂的设计与合成。药理学数据表明，化合物21具有强效的Hh通路抑制作用，其IC值为纳摩尔级别，并且它能阻止音猬因子（Shh）诱导的Smo进入初级纤毛。此外，化合物21能有效抑制突变型Smo。化合物21对耐药细胞系的抗增殖活性给出了令人鼓舞的结果。
