3‐(7‐Azaindolyl)‐4‐indolylmaleimides as a novel class of mutant isocitrate dehydrogenase‐1 inhibitors: Design, synthesis, and biological evaluation

• Published in: Archiv der Pharmazie (Weinheim) Vol. 351; no. 10; pp. e1800039 - n/a
• Main Authors: Hu, Yuanyuan, Gao, Anhui, Liao, Honghui, Zhang, Mengmeng, Xu, Gaoya, Gao, Lixin, Xu, Lei, Zhou, Yubo, Gao, Jianrong, Ye, Qing, Li, Jia
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.10.2018; Wiley Subscription Services, Inc
• Subjects: 2‐hydroxyglutaric acid; 3‐(7‐azaindoyl)‐4‐indolylmaleimides; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Dehydrogenases; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Isocitrate Dehydrogenase - antagonists & inhibitors; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; isocitrate dehydrogenase 1 inhibitors; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; tumor; SELECTIVE-INHIBITION; CELLS; IDH2 MUTATIONS; isocitrate dehydrogenase 1 inhibitors; GLIOMA; 2-hydroxyglutaric acid; ACUTE MYELOID-LEUKEMIA; 3-(7-azaindoyl)-4-indolylmaleimides; POTENT; tumor; 2 MUTATIONS; IN-VIVO; LEUKEMOGENESIS; 2-HYDROXYGLUTARATE
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201800039

A series of 3‐(7‐azainodyl)‐4‐indolylmaleimides was designed, synthesized, and evaluated for their isocitrate dehydrogenase 1 (IDH1)/R132H inhibitory activities. Many compounds such as 11a, 11c, 11e, 11g, and 11s exhibited favorable inhibitory effects on IDH1/R132H and were highly selective against the wild‐type IDH1. Evaluation of the biological activities at the cellular level showed that compounds 11a, 11c, 11e, 11g, and 11s could effectively suppress the production of 2‐hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Preliminary structure–activity relationship (SAR) and molecular modeling studies were discussed based on the experimental data obtained. These findings may provide new insights into the development of novel IDH1/R132H inhibitors. A series of 3‐(7‐azainodyl)‐4‐indolylmaleimides was designed, synthesized, and evaluated for their IDH1 mutant R132H inhibitory activities. Many compounds such as 11a, 11c, 11e, 11g, and 11s exhibited favorable inhibitory effects on IDH1/R132H and were highly selective against the IDH1 wild‐type. Compounds 11a, 11c, 11e, 11g, and 11s could effectively suppress the production of 2‐hydroxyglutaric acid in U87MG cells expressing IDH1/R132H.