ARfl/ARv7异源二聚体是驱动去势抵抗性前列腺癌（CRPC）发生及ENZ耐药的重要机制，严重危害男性健康，目前临床尚无靶向药物。我们前期研究发现，基于AR/ARv7异源二聚体独特结构设计合成的抗前列腺癌候选化合物LLU-206抗CRPC及ENZ耐药疗效显著，机制与其抑制ARfl/ARv7的蛋白水平表达有关。本项目拟进一步研究：1）研究LLU-206对多种AR/ARv7异源二聚体驱动的CRPC及ENZ耐药模型的抗前列腺癌作用；2）研究LLU-206干预AR/ARv7异源二聚体形成，促进其泛素化降解，调控其蛋白表达的分子机制；3）利用临床CRPC患者组织衍生细胞进一步验证上述研究结果。通过上述研究，阐明新型AR拮抗剂候选化合物LLU-206靶向AR/ARv7异源二聚体，改善CRPC及其耐药的全新作用机制，为新型AR/ARv7拮抗剂研发和制定合理的CRPC综合治疗方案提供理论和实验依据。

Castration-resistant prostate cancer (CRPC) and its resistance to enzaluramine driven by ARfl/ARv7 heterodimer have become a major problem in clinical. Our previous studies showed that LLU-206, a novel selective agent based on ARfl and ARv7 heterodimer structure, was significantly superior to ENZ in anti-CRPC efficacy and overcome resistance to ENZ, which might be related to its significant inhibition on the protein expression of ARfl and ARv7.This project intends to carry out the following researches: 1) Investigate the anti-prostate cancer effect of LLU-206 in multiple ARfl/ARv7-driven CRPC and ENZ resistant models; 2) Investigate the effect and mechanism of LLU-206-mediated interruption in the formation of ARfl/ARv7 heterodimer and regulation of their protein expression; 3) Further investigate the effect of LLU-206 on CRPC in clinical samples. This project will elucidate important mechanism of the novel AR antagonist candidate compound LLU-206 by targeting the formation of ARfl/ARv7 heterodimer and improving the efficiency of CRPC and ENZ resistance, further will provide theoretical and experimental basis for the development of ARfl/ARv7 targeted therapy and the formulation of rational clinical CRPC comprehensive treatment program in clinical.