新型小分子procaspase-3变构激活剂的分子构建和抗肿瘤活性评价

Caspase-3作为细胞凋亡通路的下游关键执行蛋白，在细胞凋亡信号传导中扮演着重要的作用。开发小分子药物直接激活高表达状态的procaspase-3转变为caspase-3，已成为克服中/上游凋亡蛋白突变、重启肿瘤细胞凋亡的新途径。相比较于锌离子螯合剂类procaspase-3激活剂在临床上的副作用，靶向procaspase-3变构位点的小分子激活剂表现出选择性高、副作用小等优势。化合物42的发现为设计靶向procaspase-3变构激活剂提供了可能。同时，在前期研究中，课题组已发现了一系列能增强化合物抗肿瘤活性和酶活性的脂溶性基团。因此，在继续的研究中，本课题拟基于前期研究基础和化合物42的作用模型，对化合物42进行结构优化，一方面修饰氢键结合区域；另一方面延长化合物两端的疏水区域，设计并获得具有良好生物活性和成药性的靶向procaspase-3小分子变构激活剂。

Caspase-3 plays a very important role in the apoptotic cascade as the downstream key executioner caspase. It would be ideal to identify a small molecule that directly activates procaspase-3 into active caspase-3 to induce tumor cell apoptosis. Compared to the side effects of activation of procaspase-3 by chelating zinc ion, targeting allosteric site of procaspase-3 with small molecule shows higher selectivity and less side effects. Discovery of compound 42 provided the possibility for the design of procaspase-3 allosteric activator. Also, we have reported a series of lipophilic groups that can significantly enhance the antitumor activity and enzymatic activity. Thus, in our continuing study, based on previous study and the mode of action of compound 42 and procaspase-3 allosteric site, we will design and discover novel small molecule procaspase-3 activator with targeting allosteric site by modifying and optimizing the structure of compound 42.