Design, synthesis and biological evaluation of novel morpholinopyrimidine-5-carbonitrile derivatives as dual PI3K/mTOR inhibitors. (PubMed, RSC Med Chem)
The most promising compounds 12b and 12d exhibited excellent antitumor activity against the leukemia SR cell line, which is the most sensitive cell line, with IC50 0.10 ± 0.01 and 0.09 ± 0.01 μM, respectively, along with significant effects on PI3Kα/PI3Kβ/PI3Kδ with IC50 values of 0.17 ± 0.01, 0.13 ± 0.01 and 0.76 ± 0.04 μM, respectively, for 12b and 1.27 ± 0.07, 3.20 ± 0.16 and 1.98 ± 0.11, respectively, for 12d compared to LY294002. Compared to Afinitor, these compounds inhibited mTOR with IC50 values of 0.83 ± 0.05 and 2.85 ± 0.17 μM, respectively...Compounds 12b and 12d also caused a G2/M cell cycle arrest in the leukaemia SR cell line. The findings of this study indicate that the highest effect was observed for 12b, which was supported by western blot and docking analysis.