基于雷公藤单体雷酚内酯发展治疗去势抵抗前列腺癌（CRPC）的新策略

前列腺癌（Prostate Cancer）是威胁男性健康的常见肿瘤之一，对于前列腺癌诊断和治疗研究日趋迫切。新型雄激素受体（AR）拮抗剂Enzalutamide对去势抵抗前列腺癌（CRPC）疗效显著，但GR高表达以及ARF876L突变使CRPC对Enzalutamide产生耐药。通过前期的中药成分筛选，我们发现雷酚内酯可以有效克服Enzalutamide的耐药性问题。本申请研究拟在雷酚内酯结构的基础上，利用AR和GR结合位点的相似性，结合理性分子设计、化学生物学及生物测活等技术手段，设计靶向AR和GR多靶拮抗剂，并进行进一步的作用机制研究及联合用药评价。项目的开展，将为前列腺癌的治疗提供新策略， 并将促进多靶点药物分子理性设计的发展。

Prostate cancer is one of the most common tumors that threaten male’s health. The novel developed antiandrogen drug enzalutamide shows rather effective in therapy of Castration-resistant Prostate Cancer (CRPC), however the over-expression of GR of CRPC confers the resistance of enzalutamide. Based on the previous work, we found a natural product, triptophenolide, derived from Traditional Chinese Medicine can overcome the enzalutamide resistance. Herein, based the structure of triptophenolide, we plan to develop the multi-target agent targeting AR and GR through the combination of rational drug design, chemical biology, and biological assay according to the similarity of the binding sites of GR and AR. Further, mechanism studies and the drug combination evaluation will be performed. In general, the achievement of the research work in the proposal will promote the development of the methodology in rational multi-target drug design and will provide the novel strategy in therapy of prostate cancer.