基于PD-L1活性位点可变性的小分子抑制剂发现及抗肿瘤活性研究

PD-1/PD-L1 is the most successful target in the cancer immunotherapy, there are seven approved monoclonal antibodies targeted PD-1/PD-L1. Due to the advantages of small molecule drug compared to the monoclonal antibody, it can overcome the deficiency of monoclonal antibody drugs in clinical application. But the research on PD-1/PD-L1 small molecule inhibitors is still on the beginning phase, it is still unknown whether the existing small molecule inhibitors can solve this deficiency. Therefore, discovery of the novel small molecule inhibitors targeted PD-1/PD-L1 have been the new direction in the cancer immunotherapy. This proposal discovered that PD-L1 active site was variable by the previous work. Based on that, the proposal will explore the variability of PD-L1 active site by the precise interaction study of probe molecule with PD-L1 binding pocket. The above work will give more information about the interaction between ligand and PD-L1 active site, and discover the novel active molecules. Based on analyses of interaction between small molecule inhibitor and PD-L1 active site, docking, and molecular dynamics simulation, this proposal will confirm the variable ranges of active site and then optimize the active molecules. The activity evaluation including molecular level, cellular level, pharmacodynamics in vivo, and selectivity will be used to evaluate the anti-cancer activity of compounds. The research result of this proposal will be helpful to understand the variability of PD-L1 active site and the interaction of small molecule inhibitor with PD-L1 active site. Besides, this proposal will provide the potential novel small molecule inhibitors of PD-1/PD-L1 for cancer immunotherapy.

PD-1/PD-L1是肿瘤免疫治疗领域最成功的靶点，已有7个单抗上市。小分子相对单抗的优势可以克服单抗临床应用的不足，但现有小分子药物的研究还处于起步阶段，能否解决这一不足还未知，因此开发新颖结构的PD-1/PD-L1小分子抑制剂已成为该领域的新方向。本项目基于研究发现PD-L1活性位点是可变的，拟通过探针小分子与PD-L1小分子结合口袋相互作用的精细研究，探索PD-L1活性位点的可变性，进一步解析小分子与PD-L1活性位点的相互作用，发现结构新颖的活性分子；通过活性分子与活性位点的作用力、分子对接和分子动力学模拟分析，确定活性位点的可变范围并开展活性优化；通过分子和细胞水平活性评价、体内药效学评价及选择性研究评价化合物的抗肿瘤活性。本项目有助于提高对PD-L1活性位点可变性的认识，进一步阐明小分子与活性位点的相互作用，并为肿瘤免疫治疗提供有潜力的新颖PD-1/PD-L1小分子抑制剂。

PD-1/PD-L1是肿瘤免疫治疗领域最成功的靶点，已有多个单抗药物上市。小分子抑制剂相对单抗的优势，可以克服PD-1/PD-L1单抗临床应用的不足。但是由于PD-1/PD-L1小分子活性位点研究的不足，阻碍了PD-1/PD-L1小分子抑制剂的开发，目前仍然没有小分子药物上市。. 本项目基于研究发现PD-L1上的小分子活性位点是可变的，因此设计合成了10类具有不同连接子的化合物探索PD-L1 小分子活性位点的可变性，研究结果显示PD-L1小分子活性位点的可变性是相对有限的。以PD-L1 活性位点的可变性研究中发现的苄胺连接子类小分子抑制剂为先导化合物，开展了PD-L1小分子抑制发现工作，经过化合物结构修饰、构效关系研究、结合特异性和亲和力评价、细胞水平PD-1/PD-L1相互作用阻断评价、T细胞功能评价以及人源化动物体内抗肿瘤药效学评价，获得一系列结构新颖并具有自主知识产权和开发价值的PD-L1 小分子抑制剂。. 本项目的工作提高了对PD-L1小分子活性位点的特性、空间大小、可变范围的认识，对于研究PD-L1小分子活性位点有重要科学意义；本项目的PD-L1小分子抑制发现工作可为其它PD-1/PD-L1小分子抑制剂的药物设计以及其它免疫检查点抑制剂的药物设计和研究工作提供指导。

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