New potent mTORC1/mTORC2 dual inhibitors, 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives, were obtained by optimizing functional groups on our previously reported PI3Kα inhibitor. All the target compounds were synthesized and structural optimization on the structure of the lead compound based on cytotoxic activity. The results showed that some of the target compounds exhibited moderate to high cytotoxic activity against cell line U87MG and PC-3. The activities against mTOR kinase were investigated and the compound 12q showed excellent activity with an IC₅₀ value of 54 nM in the same level of the positive control BEZ235 with IC₅₀ value of 55 nM under the same test conditions. The western blot and cell cycle results demonstrate that compound 12q is a candidate as an mTORC1/mTORC2 dual-target inhibitor. The theoretical calculations were also performed to better understanding the binding modes of the compound 12q in the mTOR active site.

通过优化我们先前报道的PI3Kα抑制剂上的官能团，可获得新的有效mTORC1 / mTORC2双重抑制剂5,7-二氢-6 H-吡咯并[2,3- d ]嘧啶-6-一衍生物。合成了所有目标化合物，并根据细胞毒性活性对前导化合物的结构进行了结构优化。结果表明，某些目标化合物对细胞系U87MG和PC-3表现出中等至高的细胞毒活性。针对mTOR激酶的活性进行了研究和化合物12Q显示出优良的活性，其IC ₅₀为54nm的值在阳性对照BEZ235相同水平的带IC ₅₀在相同的测试条件下，其值为55 nM。蛋白质印迹和细胞周期结果表明，化合物12q是mTORC1 / mTORC2双靶抑制剂的候选物。还进行了理论计算，以更好地了解mTOR活性位点中化合物12q的结合模式。