摘要
Hedgehog(Hh)信号通路在细胞增殖分化、组织形成等过程中发挥着重要的调节作用,适当的Hh信号强度及作用时间对机体各组织的正常发育至关重要,而其异常活化会导致乳腺癌、肝癌、胰腺癌、肺癌等多种恶性肿瘤的发生与发展,这使得Hh途径成为抗肿瘤药物研发的理想靶点。目前,Hh信号通路抑制剂主要作用靶点包括Hh配体、受体Smoothened(Smo)及转录因子Gli。其中,依赖于Hh配体途径的化合物因无法作用于非经典Hh信号通路仍停留在实验室研究层面;Smo蛋白的特殊结构使之能与药物高效、选择性地结合,是一个强大而有效的药物作用靶点,因而Smo选择性抑制剂一直是相关研究的活跃领域,且已有多个Smo抑制剂进入临床使用或试验阶段;Gli能调控多个致癌基因,促进细胞异常增殖而导致肿瘤的发生,还可对Hh信号通路进行反馈抑制,因此研发能够抑制Gli活性的药物具有广阔前景。在今后的研发中,可考虑设计作用于多种通路抑制剂,以避免耐药性和其他副作用的出现。
Hedgehog(Hh)signaling pathway plays an important regulatory role in the process of cell proliferation,differentiation and tissue formation.Proper intensity and action time of Hh signal are crucial for the normal development of various tissues of the body,and its abnormal activation will lead to the occurrence and development of most malignant tumors,including breast cancer,liver cancer,pancreatic cancer,and lung cancer,which makes Hh signaling pathway an ideal target for anti-tumor drug research and development.At present,the main targets of Hh signaling pathway inhibitors include Hh ligand,receptor Smoothened(Smo)and transcription factor Gli.Among them,the compounds that depend on the Hh ligand pathway still remain at the stage of laboratory research because they cannot act on the non-classical Hh signaling pathway.The special structure of Smo protein enables it to combine with drugs efficiently and selectively,which is a powerful and effective drug target.Therefore,Smo selective inhibitors have been an active field of related research,and many Smo inhibitors have entered the clinical use or trial stage.Gli can regulate multiple carcinogenic genes,promote abnormal cell proliferation and lead to tumor,and can also cause feedback inhibition to Hh signaling pathway.Therefore,the development of drugs that can inhibit the activity of Gli has broad prospects.In the future,a combination of multiple pathway inhibitors can be designed to avoid drug resistance and other side effects.
作者
刘格歌
陈旺
LIU Gege;CHEN Wang(School of Biological Science and Engineering,Shaanxi University of Technology,Shaanxi Hanzhong 723001,China;Qinba State Key Laboratory of Biological Resources and Ecological Environment,Shaanxi University of Technology,Shaanxi Hanzhong 723001,China)
出处
《中国药房》
CAS
北大核心
2023年第8期1014-1019,共6页
China Pharmacy
基金
陕西省自然科学基础研究计划项目(No.2022JM-576)
陕西省重点研发计划项目(No.2022SF-406)
陕西省教育厅服务地方专项计划项目(No.22JC024)。
