ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
Eur J Med Chem. 2020 Oct 1;203:112491. doi: 10.1016/j.ejmech.2020.112491. Epub 2020 Jul 12.
The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2 inhibitory potency than AG-221, and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2 after computational docking and dynamic simulation, which may serve as a good starting point for further development.
已证实，癌症细胞代谢途径中的酶是重要的治疗靶点，如异柠檬酸脱氢酶 2（IDH2）。本研究采用构象限制策略，以市售 IDH2 抑制剂 AG-221 为基础，设计了一系列大环衍生物。结果表明，所得到的化合物对不同的 IDH2 突变酶具有中等至良好的抑制潜力。其中，化合物 C6 对 IDH2 的抑制作用强于 AG-221，且在体外对 2-羟基戊二酸（2-HG）的抑制活性优异，其甲磺酸酯具有良好的药代动力学特性。此外，通过计算对接和动态模拟，C6 与 IDH2 具有较强的结合模式，可为进一步开发提供良好的起点。
