biostudies-literatureZapevalova MVMinistry of Science and Higher Education of the Russian Federationthe Ministry of Science and Higher Education of the Russian Federation10854https://www.ebi.ac.uk/biostudies/studies/S-EPMC9503112biostudies-literatureUnknown23(18)A (series) range of potential dimorpholinoquinazoline-based inhibitors of the <i>PI3K/Akt/mTOR cascade</i> was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound <b>7c</b> with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins. Compound <b>7c</b> inhibited the phosphorylation of Akt, mTOR, and S6K at 125-250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of <b>7b</b> 50 µM and of <b>7c</b> 500 µM and higher, that can indicate minority PI3Kα as a International journal of molecular sciencesSynthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.PMC950311213.1902.21.0004Maleev AAFonareva IPSvirshchevskaya EVKuimov ANZapevalova MVShchegravina ESFedorov AYSalnikova DIIgnatov SKGrishin IDKonovalova MVScherbakov AMSorokin DVfalseSynthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.A (series) range of potential dimorpholinoquinazoline-based inhibitors of the <i>PI3K/Akt/mTOR cascade</i> was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound <b>7c</b> with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins. Compound <b>7c</b> inhibited the phosphorylation of Akt, mTOR, and S6K at 125-250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of <b>7b</b> 50 µM and of <b>7c</b> 500 µM and higher, that can indicate minority PI3Kα as a 2022-01-01T00:00:00Z2022 Sep2026-04-08T11:48:57.929Z2025-02-19T00:44:29.375ZS-EPMC95031123614276810.3390/ijms231810854