PI3Kα is an attractive target for PIK3CA mutated malignant tumor and searching for lead compounds with novel scaffold is important for the development of PI3Kα inhibitors. Therefore, the strategy of docking-based virtual screening was performed to discovery potent inhibitors. The 4L2Y_A PI3Kα crystal structure was used as the model protein receptor due to its high docking reliability. After the multistep virtual screening protocol and biological evaluation, three hits were picked up and further similarity searching led to more potent 2-(5-(quinolin-6-yl)-1,3,4-oxadiazol-2-yl)acetamide derivatives ES-25 and ES-27. In addition, the primary SAR of these novel derivatives was discussed, which provide a basis for the further structural modification.

PI3Kα 是 PIK3CA 突变恶性肿瘤的一个有吸引力的靶标，寻找具有新型支架的先导化合物对于开发 PI3Kα 抑制剂很重要。因此，执行基于对接的虚拟筛选策略以发现有效的抑制剂。由于其对接可靠性高，4L2Y_A PI3Kα晶体结构被用作模型蛋白受体。在多步虚拟筛选方案和生物学评估之后，选取了三个命中，进一步的相似性搜索导致了更有效的 2-(5-(quinolin-6-yl)-1,3,4-oxadiazol-2-yl) 乙酰胺衍生物ES-25和ES-27。此外，还讨论了这些新型衍生物的主要 SAR，为进一步的结构修饰提供了基础。