Yevale Digambar, Buha Viralkumar, Sangani Deepkumar U, Teraiya Nishith, Sangani Chetan B, Patel Nishant
Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, PR China; Department of Chemistry, Shri M.M Patel Institute of Sciences and Research, Kadi Sarva Vishwavidyalaya, Gandhinagar, Gujarat, 382016, India.
Piramal Pharma Limited, Plot No. 18, Pharmaceutical Special Economic Zone, Village-Matoda, Taluka- Sanand, Ahmedabad, Gujarat-382213, India.
Chem Biol Interact. 2025 Oct 8;419:111635. doi: 10.1016/j.cbi.2025.111635. Epub 2025 Jul 11.
The PI3K/Akt/mTOR pathway is a key target for cancer due to its essential role in cell proliferation. This study developed quinoline compounds as a potent PI3Kδ/mTOR inhibitor and apoptosis inducer. The investigation found that 6i had the highest cytotoxicity against Raji and HeLa cells, with IC values of 0.18μM and 0.39μM, respectively. Further, 6i demonstrated substantial selectivity against dual targets PI3Kδ (IC = 0.034μM) and mTOR (IC = 0.047 μM). The kinase assay discovered that 6i had a greater selectivity for PI3Kδ/mTOR compared to PI3Ks (α, β, and γ). Molecular investigation revealed that 6i significantly reduced phosphorylated p-PI3K, p-Akt and p-RPS6 levels in Western blot, confirming PI3K/Akt/mTOR as the pathway of action. In addition, compound 6i stopped the cell cycle at the G0/G1 phase and raised total apoptosis by 16.26%. These findings were substantiated by morphological alterations in the AO/EB staining. Furthermore, 6i-treated cells increased intracellular ROS levels and reduced mitochondrial membrane polarization in a dose-dependent manner, indicating that apoptosis was mediated by a mitochondrial route. In addition, higher levels of Bax, Bax/Bcl-2 ratio, and cytochrome c also corroborated the fact that apoptosis was mediated via mitochondrial pathway. Also, treatment of compound increased fraction of caspase-3, caspase-9, and PARP-1 (excluding caspase-8), indicating that apoptosis was mediated via the intrinsic route. Besides, in silico studies had validated the anticancer effects of inhibiting PI3Kδ/mTOR. Moreover, 6i demonstrated a promising safety profile in hERG assay. Taken together, our finding suggest that 6i may be a potential candidate for further in vivo investigation.
PI3K/Akt/mTOR信号通路因其在细胞增殖中的关键作用而成为癌症的关键靶点。本研究开发了喹啉化合物作为一种有效的PI3Kδ/mTOR抑制剂和凋亡诱导剂。研究发现，6i对Raji细胞和HeLa细胞具有最高的细胞毒性，IC值分别为0.18μM和0.39μM。此外，6i对PI3Kδ（IC = 0.034μM）和mTOR（IC = 0.047μM）这两个双靶点具有显著的选择性。激酶分析发现，与PI3Ks（α、β和γ）相比，6i对PI3Kδ/mTOR具有更高的选择性。分子研究表明，6i在蛋白质印迹中显著降低了磷酸化的p-PI3K、p-Akt和p-RPS6水平，证实PI3K/Akt/mTOR为作用途径。此外，化合物6i使细胞周期停滞在G0/G1期，并使总凋亡率提高了16.26%。这些发现通过AO/EB染色的形态学改变得到证实。此外，6i处理的细胞以剂量依赖性方式增加细胞内ROS水平并降低线粒体膜电位，表明凋亡是由线粒体途径介导的。此外，较高水平的Bax、Bax/Bcl-2比值和细胞色素c也证实了凋亡是通过线粒体途径介导的这一事实。同样，化合物处理增加了caspase-3、caspase-9和PARP-1（不包括caspase-8）的比例，表明凋亡是通过内源性途径介导的。此外，计算机模拟研究验证了抑制PI3Kδ/mTOR的抗癌作用。此外，6i在hERG测定中显示出良好的安全性。综上所述，我们的研究结果表明6i可能是进一步体内研究的潜在候选药物。
