State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Bioorg Med Chem. 2019 Feb 15;27(4):589-603. doi: 10.1016/j.bmc.2018.12.029. Epub 2018 Dec 23.
A series of 3-aryl-4-indolylmaleimide IDH1/R132H inhibitors with a novel structure was obtained by high-throughput screening and structure-based optimization. Most compounds such as 7a, 7d, 7h, 7i, 7k and 7o showed high inhibitory effects on IDH1/R132H and were highly selective against IDH1/WT, IDH2/WT, GDH, GK, and FBP. Evaluation of the biological activities and function at cellular level showed that compounds 7h, 7i and 7k could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Additionally, 7h could reversed the differentiation block of the myeloid leukemic cell line, TF-1, caused by the overexpression of IDH1/R132H. We also explore the structure-activity relationship based on the experimental data, with an attempt to pave the way for future studies.
通过高通量筛选和基于结构的优化，获得了一系列具有新颖结构的 3-芳基-4-吲哚基马来酰亚胺 IDH1/R132H 抑制剂。大多数化合物，如 7a、7d、7h、7i、7k 和 7o，对 IDH1/R132H 具有高抑制作用，并且对 IDH1/WT、IDH2/WT、GDH、GK 和 FBP 具有高度选择性。在细胞水平上评估生物活性和功能的结果表明，化合物 7h、7i 和 7k 能够有效抑制表达 IDH1/R132H 的 U87MG 细胞中 2-羟基戊二酸的产生。此外，7h 能够逆转由于 IDH1/R132H 过表达而导致的髓样白血病细胞系 TF-1 的分化阻滞。我们还根据实验数据探索了构效关系，以期为未来的研究铺平道路。
