Discovery of novel potent PI3K/mTOR dual‐target inhibitors based on scaffold hopping: Design, synthesis, and antiproliferative activity

The PI3K/AKT/mTOR pathway is one of the most common dysregulated signaling cascade responses in human cancers, playing a crucial role in cell proliferation and angiogenesis. Therefore, the development of anticancer drugs targeting the PI3K and mTOR pathways has become a research hotspot in cancer treatment. In this study, the PI3K selective inhibitor GDC‐0941 was selected as a lead compound, and 28 thiophenyl‐triazine derivatives with aromatic urea structures were synthesized based on scaffold hopping, serving as a novel class of PI3K/mTOR dual inhibitors. The most promising compound Y‐2 was obtained through antiproliferative activity evaluation, kinase inhibition, and toxicity assays. The results showed that Y‐2 demonstrated potential inhibitory effects on both PI3K kinase and mTOR kinase, with IC50 values of 171.4 and 10.2 nM, respectively. The inhibitory effect of Y‐2 on mTOR kinase was 52 times greater than that of the positive drug GDC‐0941. Subsequently, the antitumor activity of Y‐2 was verified through pharmacological experiments such as AO staining, cell apoptosis, scratch assays, and cell colony formation. The antitumor mechanism of Y‐2 was further investigated through JC‐1 experiments, real‐time quantitative PCR, and Western blot analysis. Based on the above experiments, Y‐2 can be identified as a potent PI3K/mTOR dual inhibitor for cancer treatment. A series of thiophene‐triazine derivatives with aromatic urea structures were designed and synthesized based on a scaffold hopping approach. GDC‐0941 was selected as the lead compound, and the active group of PKI‐587 was introduced to design a novel class of PI3K/mTOR dual inhibitors. Pharmacological experiments have indicated that Y‐2 can be identified as a novel PI3K/mTOR dual inhibitor for cancer therapy.