基于仿生组合化学－(聚酮)吲哚生物碱的真菌合成与Aurora B抑制研究

Aurora B激酶在多种人类恶性肿瘤中过表达，是抗肿瘤药物研发的重要靶点；虽有多个Aurora B抑制剂进入临床试验，但由于种种原因，暂无品种获批上市；迫切需要寻找结构与已试化合物迥异的全新Aurora B抑制剂。吲哚是多个抗肿瘤药物的药效团，受其启发，申请人巧借真菌酶系的卓越合成修饰能力，从天然植物活性前体吲哚-3-甲醇出发，采用仿生组合合成策略，获得多个具有纳摩尔级Aurora B抑制活性的(聚酮)吲哚生物碱，并在动物模型上证明其一化合物（编号：LTr1）具有抑瘤显著、安全性好、Aurora B抑制力强等显著特点。从这些可喜苗头出发，本项目拟采用突变合成和基因挖掘技术：提升LTr1及其相关分子的得率并揭示其真菌合成途径；扩充(聚酮)吲哚分子库，结合药理评价优化发现疗效更好、安全性更强、结构全新的Aurora B抑制剂；从数个层面推动基于Aurora B特点的抗肿瘤新药发现进程。

Aurora B kinase is overexpressed in a variety of human malignant tumor tissues and has been recognized as an important target for the development of antitumor drugs. Although there are a large number of Aurora B inhibitors in clinical trials, however, for various reasons, Aurora B inhibitors have not been approved for listing so far. Therefore, it is urgent to find new aurora B inhibitors with different structures from the tested compounds. Inspired by the fact that indole is the important pharmacophore of several antitumors, starting from indole-3-methanol, a natural plant active precursor, the applicant previously adopted the excellent synthesis and modification ability of fungal enzyme system as the bionic combination synthesis to afford several indole alkaloids and polyketide-indole hybrids with nanomolar inhibitory activity against Aurora B. Among them, LTr1 with strong aurora B inhibitory activity has been proved to have remarkable antitumor effect and good safety in animal models. Based on these promising prospects, mutasynthetic strategy and silent gene mining technology will be introduced for the mycosynthesis of indole polymers LTr1 and its analogues to improve their yields, reveal their biosynthesis pathways. Furthermore, more new polyketide-indole hybrids with better aurora B inhibitory activity and stronger safety will be obtained by those methods. This project will promote the discovery of new antitumor drugs based on Aurora B target in several ways.