161P Discovery of novel 1,3,5-triazine-thiourea based dual PI3K/mTOR inhibitor against Non-small cell lung cancer (NSCLC)

Abstract

Background: The phosphatidylinositol 3-kinase (PI3K) signalling pathway plays crucial roles in cell growth, proliferation and survival, and found frequently dysregulated pathway in lung cancer. Consequently, 1,3,5-triazine based inhibitors of key kinases in the pathway, including PI3K, AKT and mTOR, have been extensively pursued in oncology in recent years. The PI3K-Akt-mTOR pathway is commonly deregulated in human malignancy including NSCLC. Therefore, the present study was aimed to develop novel 1,3,5-triazine derivatives as dual PI3K/mTOR for lung carcinoma. Methods: The 1,3,5-triazine compounds were synthesized via multi-component reaction. The compounds were tested for determination of anticancer activity against 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 for compound 7h were found to be 1.21, 2.03 and 2.86 μmol/l against A549, H157 and H52 cells, respectively. The compound 7h causes a significant increase in the number of cells in G0-G1 phase, with a corresponding decrease in the number of cells in S and G2-Mphase. It induces tumor cell apoptosis in a dose-dependent manner. The compound 7h, showed IC50 of 3.23±0.23 mMand 1.21±0.15 against PI3Ks and mTOR, 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: In conclusion, 1,3,5-triazine-thiourea has shown promising antitumor activity via attenuation of PI3K/mTOR against NSCLC and represents potential therapeutic application for further development.