Hedgehog(Hh)信号通路与多种肿瘤的发生和发展密切相关。靶向Hh信号通路受体Smoothened（Smo）的抗肿瘤药物已经研发成功，但其原发性及继发性耐药严重影响了其临床疗效。近期研究发现抑制Hh通路下游转录因子Gli有望克服现有Smo抑制剂的原发及继发性耐药，但现有Gli抑制剂活性较低，尚未进入临床研究。本课题组前期已经开展靶向Smo及Gli的抑制剂研究，获得了结构新颖、对Gli有明确抑制活性的三环先导化合物。本项目将在此基础上，通过骨架跃迁、环系收缩或扩张、侧环移动、杂原子迁移及等排替换等策略，对先导化合物进行系统的结构优化，在提高化合物对Hh通路活性基础上，验证其与Gli的作用机制，并通过体内外药效实验，考察化合物抗肿瘤活性以及克服Smo突变的能力，特别是对Smo抑制剂原发性、继发性耐药肿瘤作用，从而获得具有全新化学结构和开发前景的靶向Gli的新一代Hh通路抑制剂。

The hedgehog (Hh) signaling pathway plays a pivotal role in the embryogenesis and tissue maintenance and aberrant Hh pathway activation is involved in tumorigenesis of various cancers. Two Hh inhibitors targeting the membrane protein receptor Smoothened (Smo) have been successfully approved for treating locally advanced or metastatic basal cell carcinoma (BCC). However, resistance to these drugs is observed in considerable patients clinically, mostly due to amplification of the downstream transcription factor Gli or the resistant mutants of Smo. Our group has recently focused on the development of novel Hh inhibitors as treatment of cancers by targeting either Smo or Gli, and a new compound bearing a novel tricyclic structural scaffold, distinct from currently reported Hh inhibitors was identified as a relatively weak Gli inhibitor. This project is proposed to conduct a comprehensive medicinal chemistry campaign based on this lead compound. The mechanism of new compounds interacting with Gli, and the effects against the Smo resistant mutants will be explored..The potent compounds will be further evaluated for its in vitro and in vivo antitumor effects, and drug-like properties.