靶向转录因子Gli的新型Hedgehog信号通路抑制剂的设计、合成及抗肿瘤耐药性研究

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.

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。

髓母细胞瘤（MB）是0-14岁儿童最常见且异质性很高的恶性脑肿瘤之一，Hedgehog (Hh) 信号通路与髓母细胞瘤的发生和发展密切相关。靶向Hh信号通路受体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。本课题聚焦通过调控Hh通路最下游的转录因子Gli，解决其上游信号SMO突变导致的耐药。一方面基于抗凋亡因子Bcl-2是转录因子Gli的重要靶基因，本项目以Bcl-2上市药物Navitoclax和临床在研药物ABT-199为模板，构建了新型杂双环母核结构及含青蒿素过氧桥环等多个系列化合物，并测试其对Hh通路的调控活性。另一方面，基于BRD4可作用于Gli基因的启动子区域，本项目从已有的临床BRD4抑制剂中筛选对Gli活性较优的化合物ABBV-075，通过基于结构设计来进行新的结构优化，提高对Gli的转录调控活性。化合物SOMCL-5-23是一个强效的BRD4和Hh通路抑制剂，其IC50值为0.48 nM，同时SOMCL-5-23对SMO野生型和两种主要耐药突变体（SMOD473H和SMOW535L）均具有同等的活性，IC50值约为1 nM或更小。在SMO拮抗剂耐药的SMOA1 MB小鼠模型中，化合物SOMCL-5-23表现出好的耐受性，在5 mg/kg (TGI = 83.3%)和10 mg/kg (TGI = 87.6%)剂量下均可显著抑制肿瘤生长。相对于对耐药无效的SMO拮抗剂Vismodegib和BRD4抑制剂ABBV-075，新型Gli抑制剂SOMCL-5-23是一种更安全、更耐受的对抗Hh驱动的MB的候选化合物，尤其是对当前SMO拮抗剂耐药的MB。