Discovery of novel bis-aryl urea-linked triazine derivatives as dual PI3K/mTOR inhibitors via scaffold hopping strategy and biological activity evaluations.

Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are overexpressed in breast cancer and drive oncogenesis, rendering PI3K/mTOR inhibitors as promising therapeutic agents. However, tumor cells readily develop resistance to single-agent PI3K or mTOR inhibitors. In this study, 40 novel bis-aryl urea-linked triazine derivatives were designed and synthesized as dual PI3K/mTOR inhibitors using a scaffold hopping strategy. Their biological activities were evaluated. The results showed that J-33 was a dual inhibitor of PI3K and mTOR kinases, with IC values of 400.5 nM and 8.2 nM, respectively, and it inhibited other tested kinases by less than 50%. The antiproliferative IC value of J-33 against MCF-7 cells was 1.5 ± 0.2 μM. Hemolysis assays indicated that J-33 exhibited low hemolytic toxicity. Apoptosis and AO staining experiments demonstrated that J-33 induced apoptosis in MCF-7 cells in a concentration-dependent manner. Western blot analysis showed that J-33 significantly downregulated the phosphorylation level of the PI3K-AKT-mTOR pathway. Therefore, we conducted in vivo antitumor studies using a nude mouse model with MCF-7 cell xenografts. The results demonstrated that at the same dose of 75 mg/kg, J-33 exhibited a higher tumor inhibition rate (44.9%) compared to PKI-587 (43.6%). In summary, a highly potent and low-toxic dual PI3K/mTOR inhibitor was developed, which deserves further investigation.