基于片段的药物发现方法是高成药率的新药研发策略，但是在蛋白质相互作用抑制剂的分子设计和结构优化中还面临挑战。本项目拟将该方法用于广谱Bcl-2蛋白抑制剂类抗癌候选药物的研究，在我们已经证明的氰基乙酰胺片段分子与Bcl-2的结合模式的基础上，进行分子组装、生长、融合等结构优化，对优化过程中的小分子进行荧光偏振、等温量热滴定、蛋白质二维核磁、细胞试验等生物学活性评价，通过研究、分析、生物学活性数据，计算LE（配体效率），BEI(结合效率)，ΔG（结合能）等参数，绘制多种参数相对于分子量增长的函数关系曲线，发现能够预测优化成功的函数曲线，建立该方法用于广谱Bcl-2蛋白抑制剂研究的定量的生物学活性评价方法，通过实现可监控的分子设计和优化，提高基于片段方法在蛋白质相互作用抑制剂领域的可行性。同时，还将获得新结构、高活性、类药性好、具有体内活性的广谱Bcl-2抑制剂，有希望成为原创分子靶向抗癌药。

Although fragment-based drug discovery is a potent and promising strategy, it is challenged in the development of inhibitors of protein-protein interaction. We aimed to apply this method in pan-bcl-2 inhibiting antitumor leading drugs. Based on the binding mode of cyanoacetamide with the targeted proteins, molecular growing and molecular assembly will be performed. All the compounds will be assayed by ITC, FP, 1H-15N HSQC, and cell-based experiments. The analysis of LE, BEL, and ΔG would lead to quantitative assessment of hit-to-lead. An fragment-based quantitative evaluation method for pan-Bcl-2 inhibitors could be establied through this project, which could promote the development of fragment-based drug discovery in Bcl-2 inhibiing antitumor drugs and then accelerate the success of this kind of targeted antitumor drugs. Additionally, the new scaffold, drug-like, effective in vivo, and pan-Bcl-2 inhibitors obtained by this project could be developed as target antitumor drugs.