Bcl-2家族蛋白共价抑制剂——基于结构的分子设计和共价修饰“弹头”的筛选

Bcl-2家族蛋白是肿瘤靶标蛋白。Bcl-2和Mcl-1蛋白通过与促凋亡蛋白的蛋白-蛋白相互作用（PPI）调控细胞凋亡。申请人拟在自主研发的Bcl-2蛋白非共价抑制剂的分子骨架上连接亲电基团，共价结合Bcl-2蛋白和/或Mcl-1蛋白上的亲核氨基酸残基，首次获得特异性Bcl-2蛋白共价抑制剂、特异性Mcl-1蛋白共价抑制剂和Bcl-2/Mcl-1共价双抑制剂分子。通过与靶蛋白上的氨基酸残基发生不可逆结合，显著增强小分子的亲和力，突破PPI靶标抑制剂亲和力普遍偏低这一瓶颈，获得更高抗肿瘤活性的候选药物。本研究还将筛选和评价具有多样性的共价修饰“弹头”，丰富亲电基团的种类和共价修饰氨基酸残基的反应类型。通过分析结合动力学参数与共价抑制剂分子的特异性、亲和力和脱靶毒性的关系，为Bcl-2家族PPI共价抑制剂以及其它PPI靶标共价抑制剂提供“弹头”的分子设计原则。

Bcl-2 family proteins are tumor target proteins. Anti-apoptotic Bcl-2 and Mcl-1 regulate cellular apoptosis via protein-protein interactions (PPIs) with pro-apoptotic proteins. A targeted covalent inhibitor (TCI) is designed such that the initial, reversible association is followed by the formation of a covalent bond between an electrophile on the ligand and a nucleophilic center in the protein. Herein, we planned to incorporate electrophile “warheads” into S1, a noncovalently Bcl-2 family inhibitor, which would allow site-specific covalent modification of Bcl-2 family proteins’ nucleophilic residues and provide potential covalent Bcl-2 family inhibitors as drug leads for targeted cancer therapy. Covalent inhibition was utilized to overcome the increased affinity of the PPI inhibitors. Moreover, a variety of novel electrophilic “warheads” will be discovered for covalent inhibitors design. Finally, we also will discuss the importance of the rate of covalent modification, in interpreting structure-activity relationships (SARs), translating activity from biochemical assays to the cell and more accurately defining selectivity.