Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar-382355, Gujarat, India.
Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar-382355, Gujarat, India.
Molecules. 2018 Apr 24;23(5):992. doi: 10.3390/molecules23050992.
Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR). These kinases induce cell cycle arrest in response to chemo- and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC = 250 pmol/L) with better pharmacokinetic profile. Torin2 also exhibits potent biochemical and cellular activity against ATM (EC = 28 nmol/L) and ATR (EC = 35 nmol/L) kinases. In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass analysis. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo assay. Additionally, compounds and also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, respectively. Compounds and displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server and validated using PROCHECK, ProSA analysis. Synthesized compounds were docked into the ATP-binding site to understand the binding modes and for the rational design of new inhibitors.
靶向 DNA 损伤反应 (DDR) 途径已成为癌症治疗的一种有吸引力的方法。该途径中的关键介质包括共济失调毛细血管扩张突变激酶 (ATM) 和共济失调毛细血管扩张突变、Rad3 相关激酶 (ATR)。这些激酶通过其主要下游靶点诱导化疗和放疗后的细胞周期停滞，并促进 DNA 修复。目前正在研究靶向这些激酶的 ATP 结合位点。Torin2 是第二代 ATP 竞争性 mTOR 激酶抑制剂（EC=250pmol/L），具有更好的药代动力学特性。Torin2 对 ATM（EC=28nmol/L）和 ATR（EC=35nmol/L）激酶也表现出很强的生化和细胞活性。在这项研究中，通过多步合成设计并合成了 8 种新的 Torin2 类似物。所有合成的化合物均通过 NMR 和质谱分析进行了表征。通过 CellTiter-Glo 测定法评估了新合成的类似物的抗癌活性。此外，化合物和也对 ATR 和 mTOR 底物，即 p-Chk1 Ser317 和 p70S6K Thr389，表现出显著的抑制作用。在初步研究中，化合物和对 HCT-116 细胞系显示出有希望的抗癌活性。此外，使用 SWISS-MODEL 服务器生成了 ATR 激酶的比较模型，并使用 PROCHECK、ProSA 分析进行了验证。将合成的化合物对接入 ATP 结合位点，以了解结合模式并为新抑制剂的合理设计提供依据。
