靶向瞬时受体电位阳离子通道6选择性抑制剂的发现及其抗前列腺癌机理研究

功能重塑的离子通道在前列腺癌（PC）发生和进展中发挥重要作用，已成为PC的潜在药靶。PC中表达增高的瞬时受体电位阳离子通道6（TRPC6）可促进PC细胞的增殖，但其可否成为PC的药靶及其在PC中的调控网络尚不清楚。项目组前期获得具有TRPC6较高选择性抑制的化合物1ac，并证实它可抑制PC细胞异体移植瘤的生长，且与TRPC6显示出较强的结合能力。本项目在基于1ac与TRPC6结合数据进行结构优化的同时，通过测定新化合物对PC细胞存活通路、迁移、血管新生等的影响及其与抑制TRPC6的相关性以明确新化合物的靶点，并通过蛋白-抑制共结晶探索其与TRPC6的结合位点。最后通过基因芯片检测等手段探索新化合物抗PC的分子机制并揭示TRPC6在PC中的调控网络及其在维持或促进PC进展中的作用。本项目的完成将为以TRPC6为靶标的PC治疗药物研究提供理论依据，并有望发现TRPC6抑制剂新的作用位点。

The remodeled ion channel plays an important role in the carcinogenesis and progression of prostate cancer (PC), and is considered as a potential drug target against PC. The transient receptor potential cation channel 6 (TRPC6) has been shown to be overexpressed in PC and to promote the proliferation of PC cells. The facts, whether TRPC6 is a druggable target against PC as well as its molecular regulations within PC, keep unclear. In our previous study, one novel phenylthiazolamide compound, designated as 1ac, is designed and synthesized, which has showed high inhibitory activity against PC with high selective inhibitory activity against TRPC6. At the same time, the docking data shows 1ac could directly bind with TRPC6. In this project, 1ac is further optimized to find more potential chemical based on its docking profiles with TRPC6. The effect of novel compound on the survival pathway, migration and angiogenesis, as well as the correlation between its activities mentioned above and its effect on the activity of TRPC6 will be studied to validate its target. After that, the binding mode and binding site of the novel compound within TRPC6 will be explored using cryogenic electron microscopy. Finally, the molecular mechanism of novel compound against PC is explored using chip, RNA-seq et al to unveil the regulatory network of TRPC6 within PC as well as the potential role of TRPC6 in maintaining and/or promoting the progression of PC. The completion of this project will provide a theoretical basis for the drug discovery against PC targeting TRPC6, and the potential novel binding site of TRPC6 antagonist within TRPC6 might be discovered.