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- W2586591134 abstract "Background The phosphatidylinositol 3-kinase (PI3K) signallingpathwayplays crucial roles in cell growth, proliferation and survival, and found frequently dysregulatedpathwayinlungcancer.Consequently,1,3,5-triazinebasedinhibitorsof key kinases in the pathway, including PI3K, AKT and mTOR, have been extensively pursuedinoncologyinrecentyears.ThePI3K-Akt-mTORpathwayiscommonly deregulated in human malignancy including NSCLC. Therefore, the present study was aimedtodevelop novel1,3,5-triazinederivativesasdualPI3K/mTOR forlung carcinoma. Methods:The1,3,5-triazinecompoundsweresynthesizedviamulti-component reaction. Thecompounds weretestedfordetermination ofanticanceractivityagainst three human NSCLC cell lines A549, H157 and H52. The compounds were also tested for effect on cell growth inhibition and apoptosis through cell cycle arrest assay. The compounds were tested for inhibitory activity against PI3Ka and mTOR via kinase inhibition assay. The docking analysis was also carried out with PI3K and mTOR domain to elucidate vital structural residues necessary for bioactivity. Results The compounds were developed in excellent yield. The cytotoxicity studies suggests that, synthesized derivatives exhibit considerable inhibition with average IC50 forcompound7hwerefoundtobe1.21,2.03and2.86mmol/lagainstA549,H157and H52 cells, respectively. The compound 7h causes a significant increase in the number of cells in G0-G1 phase, withacorrespondingdecrease in the number ofcells in S and G2- Mphase.Itinducestumorcellapoptosisinadose-dependentmanner.Thecompound 7h,showedIC50of3.2360.23mMand1.2160.15againstPI3KsandmTOR, respectively. Whereas, the docking results showed that compound 7h, 7l, 7m, 7e were found to be the most efficient analogues to inhibit PI3Ks and mTOR by binding the ATP pocket via creating interactions with ASP2195, ASP2357, LYS802 and ASP810. Conclusions:Inconclusion,1,3,5-triazine-thioureahasshownpromisingantitumor activityviaattenuationofPI3K/mTORagainstNSCLCandrepresentspotential therapeutic application for further development. Legal entity responsible for the study SHIATS Funding SHIATS Disclosure All authors have declared no conflicts ofinterest." @default.
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- W2586591134 date "2016-12-01" @default.
- W2586591134 modified "2023-10-18" @default.
- W2586591134 title "161P Discovery of novel 1,3,5-triazine-thiourea based dual PI3K/ mTOR inhibitor against Non-small cell lung cancer (NSCLC)" @default.
- W2586591134 doi "https://doi.org/10.1016/s0923-7534(21)00319-7" @default.
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