蛋白-蛋白相互作用小分子探针设计、合成和生物活性研究

The discovery of new, effective small molecules targeting protein-protein interaction (PPI) demands the expansion of chemical space beyond the current domain. The new chemical structures generally possess natural product-like complex molecular architectures enriched with rings, stereogenic centers and functional groups. Such structures can effectively interrupt PPI due to their large interaction surface and multiple forces involved in the interactions. However, these structural features present daunting synthetic challenges in the construction of the complex molecules. Toward this end, we propose to develop new efficient synergistic cascade catalysis strategies by the integration of two distinct catalytic systems in one operation to rapidly create novel natural product-like complex frameworks, enriched with ring structures, stereochemical and functional diversity. It will be demonstrated that more than 30 new, distinct highly complex skeletons containing at least 3 rings and more than 4 chiral centers will be facilely assembled. These scaffolds will be docked on PPI MDM2/p53 and KRAS/PDEδ and new derivatives with incorporation of functional groups into the identified frameworks will be rationally designed by computer-aided drug design and synthesized for biological evaluation. Potent and selective compounds found from above studies will be selected for further SAR studies to lead to the promising molecules for further evaluation as potential anti-tumor drug candidates and the action of mechanism studies. The successful accomplishment of the innovative project by integrating the cutting edge technologies of modern organic synthesis and medicinal chemistry will build a new drug discovery platform for the facile identification of inhibitors as potential therapeutic agents challenging PPI targets.

发现结构新颖的蛋白-蛋白相互作用(PPI)小分子探针/抑制剂亟需拓展新化学空间，而有效的PPI探针/抑制剂要求含有多环、多手性中心和多官能团的复杂结构。本项目致力于发展新型有机和金属协同催化的高效串联合成策略，快速构建具有新化学空间的复杂分子骨架，并兼容丰富的官能团，优势结构和药效基团。通过串联反应和进一步化学转化，快速得到30多种包含至少3个环系和4个以上手性中心的结构复杂度各异的新型分子骨架。基于这些骨架，针对抗肿瘤PPI靶标MDM2/p53和KRAS/PDEδ开展合理分子设计、生物活性评价和作用机制研究，发现全新结构的PPI抑制剂。在此基础上进行构效关系研究和结构优化，获得抗肿瘤先导化合物或候选药物。本项目体现了现代有机合成方法学和药物化学的交叉融合，为多样性分子骨架构建和PPI小分子抑制剂设计提供全新的研究策略，而且有望发现有药用价值的新化学实体，为开发新一代抗肿瘤药奠定基础。

本项目致力于发展新型催化合成策略特别是串联反应，快速构建了10多种具有新化学空间的复杂分子骨架，并兼容丰富的官能团，优势结构和药效基团。通过串联反应和进一步化学转化，快速得到结构复杂度各异的新型分子骨架，合成了600多个化合物的化学库。针对抗肿瘤PPI靶标MDM2/p53和KRAS/PDEδ开展合理分子设计、生物活性评价和作用机制研究，发现全新结构的PPI抑制剂。基于p53/MDM2、KRAS/PDEδ、BET BRD4等蛋白-蛋白相互作用靶点，设计和优化了新型小分子抑制剂，设计合成新化合物100余个。发现6个具有自主知识产权，在分子/细胞/动物水平均具有优秀活性抗肿瘤先导化合物，显示了良好的成药性能。从中优选得到具有优良PK/PD性能的BET-HDAC抑制剂，有望成为抗胰腺癌候选新药。基于p53-MDM2蛋白-蛋白相互作用，提出了MDM2-HDAC双靶抑制剂和MDM2 Homo-PROTAC设计新策略，获得了体内外活性优秀的新药候选分子。基于KRAS- PDE蛋白-蛋白相互作用，合理设计得到具有pM级活性的小分子抑制剂，并且首次在胰腺癌PDX模型中显示出药效。设计得到首个靶向降解PDE的PROTAC分子，展示了优良的体内外活性。本项目获得授权专利7件和申请2件，发表论文44篇。