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U.P. Singh

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    Poster Display Session (ID 63)

    • Event: ELCC 2017
    • Type: Poster Display Session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 5/07/2017, 12:30 - 13:00, Hall 1
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      41P - Development of novel 1,2,4-triazole-thiol derivatives as dual PI3K/mTOR inhibitor against the non-small cell lung cancer (NSCLC) (ID 435)

      12:30 - 13:00  |  Author(s): U.P. Singh

      • Abstract

      PI3K catalyzes the ATP-dependent phosphorylation of the 3'-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. However, most of the inhibitors in this signaling pathway have inhibitory effect against both PI3K and mammalian target of rapamycin (mTOR) kinases. It is well known that the mTOR, regulate cell proliferation, apoptosis, angiogenesis, and metabolism through both AKT-dependent and AKT-independent mechanisms. Agents targeting PI3Ks with additional mTOR kinase inhibitory have more advantageous than alone inhibition. Our efforts to identify potent and efficacious PI3K/mTOR dual inhibitors resulted in the discovery of a series of substituted 1,2,4-triazole-thiol derivatives.

      The entire set of the designed compounds were assessed on the Lipinski rule of five for drug-likeness prediction using Molinspiration and synthesized via novel synthetic procedure. The anticancer activity was evaluated against panel of three human NSCLC cell lines A549, H157 and H52 together with effect on cell cycle. The compounds were also evaluated for inhibitory activity against PI3K and mTOR via kinase inhibitory assay together with molecular docking experiments (PI3K; 3s2a.pdb) to rationalize the mechanism of action.

      The compounds were developed in excellent yield and found to be significantly activity against the panel of the cell lines. The most active compound 6b showed significant inhibitory activity with IC50 of 4.56, 7.23 and 9.21 µmol/l against A549, H157 and H52, respectively, with highest activity against A549 (IC50 = 1.13 µmol/l). The compound 6b causes a significant arrest of G2/M phase and induces tumor cell apoptosis in a concentration dependent manner. In a PI3K/mTOR inhibition assay, 6b showed IC50 of 1.43±0.21 µM and 2.32±0.12 against PI3Ks and mTOR, respectively. Moreover, the docking results showed that 6b efficiently inhibit PI3Ks via channeling in ATP pocket with Ki of 436.57 nM. It showed to interact with Met804, ILE831, ILE879.

      In conclusion, a novel series of 1,2,4-triazole-thiol derivatives has been developed as potent inhibitor of PI3K/mTOR against lung cancer with favorable drug likeness profile.

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      All authors have declared no conflicts of interest.