靶向AR-FL/AR-V7的汉黄芩素衍生物的结构优化及其在去势抵抗性前列腺癌CRPC中的应用

本项目提出同时靶向AR全长（AR-FL）和其主要剪切变异体AR-V7是治疗去势抵抗前列腺癌药物研发的有效策略。在分子生物学层次上降低AR-FL/AR-V7蛋白的表达水平有望克服临床上所存在的患者不敏感以及耐药性等问题。本项目前期发现了兼具AR拮抗作用及AR-FL/AR-V7降解作用的汉黄芩素衍生物LLU-206，其在体内外表现出良好的抗肿瘤活性及安全性。本项目拟以LLU-206为先导物，对其进行结构改造，深入研究“构-效”关系。此外，为克服其母环骨架稳定性较差、药代性质不佳等问题，将在最优骨架基础上进行功能取代基配置方案的探索，以期获得高效、低毒、具有良好成药性的靶向AR-FL/AR-V7的小分子调控剂作为抗CRPC候选新药。同时，本项目将对活性最优的拮抗剂/降解剂进行生物机制学研究以探讨AR-FL及AR-V7以何种机制识别小分子配体产生降解作用，为后续小分子调控剂的研究提供理论依据。

In this project we propose that it would be a promising strategy for the treatment of castration-resistant prostate cancer (CRPC) that simultaneously targeting full-length androgen receptor (AR-FL) and androgen receptor splice variant-7 (AR-V7). Degrading the level of AR-FL/AR-V7 is expected to overcome drug resistance and insensitivity in clinical patients. Previously, we have discovered a derivative of natural product Wogonin LLU-206, which has potent AR antagonistic activity and ARfl/AR-V7 degradation efficacy, and exhibits potent antitumor activity and safety in vitro and in vivo. Based on the scaffold of LLU-206, we will further carry out a more comprehensive structural modification and further explore the structure activity relationship through the chemical informatics, chemical biology and medicinal chemistry. Moreover, in order to improve the metabolic stability, drug-like and pharmacokinetic properties, we have explored different arrangements for the substituents in parent scaffold. We prospect to discover potent AR-FL/AR-V7 modulators with novel structure, high potency, and satisfied tolerability in preclinical models and may be the novel candidate drugs against CRPC. In addition, the most promising compound would be employed for further biological mechanism study to explore the correlation between AR-FL/AR-V7 and ligands. The conclusion could be reference for the next generation AR-FL/AR-V7 modulators.