Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China.
Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China; School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510000, China.
Bioorg Chem. 2022 Dec;129:106157. doi: 10.1016/j.bioorg.2022.106157. Epub 2022 Sep 27.
Blocking the PI3K/AKT/mTOR pathway has been widely recognized as an attractive cancer therapeutic strategy because of its crucial role in cell growth and survival. In this study, a novel series of 2-arylurea-1,3,5-triazine derivatives had been synthesized and evaluated as highly potent PI3K and mTOR inhibitors. The new compounds exhibited cytotoxic activities against MCF-7, Hela and A549 cancer cell lines (IC = 0.03-36.54 μM). The most promising compound XIN-9 exhibited potent inhibition against PI3K and mTOR kinase (IC = 23.8 and 10.9 nM). Mechanistic study using real-time PCR revealed the ability of XIN-9 to inhibit PI3K and mTOR. In addition, compound XIN-9 arrested the cell cycle of MCF-7 cells at the G0/G1 phase. XIN-9 also caused a significant dose-dependent increase of early and late apoptotic events. Molecular docking analysis revealed a high binding affinity for XIN-9 toward PI3K and mTOR. Following in vitro studies, XIN-9 was further evaluated in MCF-7 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 41.67% (po, 75 mg/kg). Overall, this work indicated that compound XIN-9 represents a potential anticancer targeting PI3K/AKT/mTOR pathway.
阻断 PI3K/AKT/mTOR 通路已被广泛认为是一种有吸引力的癌症治疗策略，因为它在细胞生长和存活中起着至关重要的作用。在这项研究中，我们合成了一系列新型的 2-芳基脲-1,3,5-三嗪衍生物，并将其评估为高效的 PI3K 和 mTOR 抑制剂。新化合物对 MCF-7、Hela 和 A549 癌细胞系表现出细胞毒性活性（IC = 0.03-36.54 μM）。最有前途的化合物 XIN-9 对 PI3K 和 mTOR 激酶表现出强大的抑制作用（IC = 23.8 和 10.9 nM）。使用实时 PCR 的机制研究表明，XIN-9 能够抑制 PI3K 和 mTOR。此外，化合物 XIN-9 将 MCF-7 细胞的细胞周期阻滞在 G0/G1 期。XIN-9 还导致早期和晚期凋亡事件的显著剂量依赖性增加。分子对接分析表明，XIN-9 与 PI3K 和 mTOR 具有高结合亲和力。在体外研究之后，XIN-9 在 MCF-7 异种移植模型中进一步进行了评估，结果表明，XIN-9 具有显著的体内抗癌疗效，肿瘤生长抑制率为 41.67%（po，75 mg/kg）。总的来说，这项工作表明，化合物 XIN-9 代表了一种潜在的针对 PI3K/AKT/mTOR 通路的抗癌药物。
