利用小分子p53-BH3功能模拟物研究Bcl-2-like/p53二聚体调控内源凋亡的分子机制

p53是一种重要的肿瘤抑制因子，其通过Bcl-2家族蛋白发挥的转录非依赖抗肿瘤作用日益受到关注。但是， p53蛋白与Bcl-2-like蛋白通过蛋白质间相互作用调控细胞凋亡的分子机制至今未能阐明。本研究将筛选并利用能够解离Bcl-2-like/p53二聚体的p53-BH3功能模拟物，作为直接的小分子工具，通过体外无细胞体系和细胞试验，揭示Bcl-2-like/p53二聚体调控内源凋亡的分子机制；发现和确认Bcl-2-like/p53作为新的抗肿瘤靶标；解读Bcl-2家族蛋白与p53信号通路的交互对话机制，指导同时拮抗p53和Bcl-2蛋白的联合用药抗肿瘤策略。此外，通过对p53-BH3功能模拟物的构效关系研究，还将获得p53-BH3功能模拟物别构调节Bcl-2-like蛋白，调控Bcl-2-like/p53二聚体的关键结构信息，为药物分子设计提供新的结构基础。

p53 is a prominent tumor suppressor.p53 can crosstalk with Bcl-2 family proteins and promote apoptosis through transcription-independent mechanisms. The analysis of transcription-independent pathways in p53-mediated apoptosis has emerged as an intensive area of research. However, the molecular mechanisms of apoptosis regulation by the interaction between p53 and Bcl-2-like proteins remain unclear. In order to reveal the biological function and significance of Bcl-2-like/p53 dimer, the subject is committed to acquire the first small molecule tools (p53-BH3 mimetics) that directly disrupt Bcl-2-like/p53, to directly study the mechanisms of intrinsic apoptosis regulation by Bcl-2-like/p53. Using these small molecule tools, we would study the apoptosis mechanism regulated by p53 and Bcl-2 family proteins on cell free system and cellular model. The subject could not only discover and confirm Bcl-2-like/p53 as a new anti-tumor drug target, but also illuminate the crosstalk between Bcl-2 family and p53 which will provide new therapeutic targets and a potential drug combination for targeted cancer therapy. In addition, through the structural-activity relationship study of these p53-BH3 mimetics, we would acquire allosteric regulation structural information of the interaction between Bcl-2-like and p53, and provide new structure bases for drug design.