A novel quinolinebased second-generation mTOR inhibitor that induces apoptosis and disruptsPI3K-Akt-
Deregulation of the PI3K-Akt-mTOR pathway is unanimouslypragmatic in a number of tumors. This pathway pedals proliferation, survival,translation, and coupledwithtumor-associated endurance. Current efforts focus on the discovery and developmentofnovel inhibitors of this pathway. We have discovered6-(4-phenoxyphenyl)-N-phenylquinolin-4-amine [PQQ] as a potentmTOR inhibitor with IC50 value of 64 nMin a cell-based andcell-free mTOR assay. Mechanistically, PQQfoundto be a strong PI3K-Akt-mTOR-p70S6Kcascadeinhibitorin Human promyelocytic leukemia HL-60 cells.Moreover, it found to be dual mTORC1 and mTORC2 inhibitor that inhibit the entiremTORkinase-dependent functions and feedback commencementof PI3K/Aktpathway.PQQ simultaneously induces apoptosis via mitochondrial dependant pathway, which was confirmed through a battery of the assay, e.g. cellular and nuclear microscopy, annexin-V assay, cell cycle analysis, and loss of mitochondrial membrane potential. In summary, PQQdiscovered as a novel second-generationmTOR inhibitor with significant cytotoxic and apoptotic potentials. Thus, it might be a significant lead structure for the development of mTOR-targeted based anti-cancer therapeutics.
A novel quinolinebased second-generation mTOR inhibitor that induces apoptosis and disruptsPI3K-Akt-mTOR signaling in human leukemia HL-60 cells Anticancer Agents Med Chem. 2015 April