2. Academic Validation
  3. Identification and structure-activity relationship optimization of dibromoacetophenones as novel mIDH1 inhibitors

Identification and structure-activity relationship optimization of dibromoacetophenones as novel mIDH1 inhibitors

  • Eur J Med Chem. 2025 Dec 5:299:118050. doi: 10.1016/j.ejmech.2025.118050.
Cong Li 1,  Min Yang 1,  Zhiying Cui 1,  Haibo Yan 1,  Jiaming Ou 1,  Biao Xu 2,  Yuwei Wang 3,  Yun He 4,  Shao-Lin Zhang 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: xubiao@cqmu.edu.cn.
  • 3 College of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, 712046, PR China. Electronic address: wangyw@sntcm.edu.cn.
  • 4 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China; BayRay Innovation Center, Shenzhen Bay Laboratory, Shenzhen, 518132, PR China.
  • 5 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China. Electronic address: zhangsl@cqu.edu.cn.
PMID: 40803168 DOI: 10.1016/j.ejmech.2025.118050
Abstract

Mutations at arginine 132 in isocitrate dehydrogenase 1 (IDH1) are prevalent in various cancers, making them attractive therapeutic targets. Here, we report the discovery and optimization of a novel dual inhibitor. Initial screening of an in-house library identified lead compound 1-1, which inhibited IDH1 R132H by 73.6 % at 2 μM. Iterative SAR efforts yielded compound 27j with subnanomolar potency against IDH1 R132H and R132C (IC50 = 80.0 and 58.0 nM) and minimal activity against wt-IDH1/2. Notably, 27j also inhibits PDK1 (IC50 = 0.61 μM), reducing PDH phosphorylation dose-dependently. It significantly suppressed 2-HG production in U87-MG IDH1 R132H and HT1080 cells (EC50 = 69.0 and 121.1 nM). In phenotypic assays, 27j inhibited U87-MG IDH1 R132H cell proliferation (GC50 = 1.4 μM), induced S-phase arrest, and promoted Apoptosis, with limited toxicity to normal L02 cells. These results highlight 27j as a potent mIDH1/PDK1 dual inhibitor for further development.

Keywords

Isocitrate dehydrogenases 1; Pyruvate dehydrogenase kinase; Structure-activity relationship study.

Figures
Products