Design, synthesis and biological evaluation of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as potential dual PI3K α/mTOR inhibitors.

Design, synthesis and biological evaluation of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as potential dual PI3Kα/mTOR inhibitors. Bioorg Chem. 2019 Dec 20;95:103525 Authors: Zhang B, Zhang Q, Xiao Z, Sun X, Yang Z, Gu Q, Liu Z, Xie T, Jin Q, Zheng P, Xu S, Zhu W Abstract The phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been regarded as promising targets for the treatment of cancer. Herein, we synthesized a new series of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as novel PI3Kα/mTOR dual inhibitors for cancer therapy. All compounds were evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and Hela). Most of the target compounds exhibited moderate to excellent anti-tumor activities against these three tested cancer cell lines especially against A549 and Hela cancer cell lines. Among them, the most promising compound 13g showed excellent anti-tumor potency for A549, MCF-7 and Hela cell lines with IC50 values of 0.20 ± 0.05 µM, 1.25 ± 0.11 µM and 1.03 ± 0.24 µM, respectively. Notably, according to the result of enzymatic activity assay, compound 13g was identified as a novel PI3Kα/mTOR dual inhibitor, which had an approximately 10-fold improvement in mTOR inhibition, compared to the class I PI3K inhibitor 1 (pictilisib, GDC-0941), with IC50 values of 525 nM to 48 nM. And western blot analysis indicated compound 13g could efficiently s...
Source: Bioorganic Chemistry - Category: Chemistry Authors: Tags: Bioorg Chem Source Type: research