免疫亲和蛋白（FKBP51）和雄激素受体（AR）激活与去势抵抗性前列腺癌（CRPC）发生相关。前期我们筛选获得了FKBP51靶向抑制剂对硝基苯酚（PNP）和雷帕霉素（RPM）可通过结合FKBP51抑制前列腺癌(PCa)。我们将构建PCa/CRPC细胞与动物模型，用蛋白质荧光淬灭实验、表面等离子体共振、细胞高内涵分析、X射线衍射、流式细胞、化学信息和多种分子生物学技术研究：PNP和RPM与FKBP51的结合方式、活性构效关系和结合动力学过程；PNP和RPM对PCa/CRPC细胞和干细胞及CRPC实验动物肿瘤抑制的作用；通过抑制FKBP51对CRPC密切相关的AR-V7、PI3K/Akt和NF-κB的调控作用；PNP和RPM对PCa/CRPC细胞代谢、肿瘤微环境和肿瘤侵袭的影响；对比或协同抗雄药物的作用和副作用。为基于FKBP51抑制剂治疗PCa/CRPC提供分子结构基础和临床思路。

Immunophilin FKBP51 is deeply involved in AR activity and CRPC develpment. In previous studies, we screened two FKBP51 inhibitors, p-nitrophenol (PNP) and rapamycin (RPM), which can inhibit prostate cancer by binding to FKBP51. We will construct the cell and animal models of PCa/CRPC and apply multiple methods including protein fluorescence quenching experiments, surface plasmon resonance, cell high content analysis, X-ray diffraction, flow cytometry, chemical informatics and various molecular biology techniques to investigate the binding modes, structure-acitvity relationship and the kinetics of binding between PNP and RPM with the target FKBP51; to investigate the tumor suppression effects of PNP and RPM on PCa/CRPC cells, prostate cancer stem cells and CRPC animals; to confirm the regulation effect on PCa/CRPC related AR-V7, PI3K/Akt and NF-κB by inhibiting FKBP51; to study the influences on cell metabolism, tumor microenvironment and tumor invasion of PCa/CRPC by RPM and PNP; to evaluate the synergy and side effects of RPM and PNP together with anti-androgen drugs. These investigations will provide molecular structure basis and clinical clues for FKBP51 inbihitor based CRPC treatment.