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  3. Discovery and structure-activity relationship study of novel hydantoin-based inhibitors targeting mutant isocitrate dehydrogenase 1 (mIDH1)

Discovery and structure-activity relationship study of novel hydantoin-based inhibitors targeting mutant isocitrate dehydrogenase 1 (mIDH1)

  • Eur J Med Chem. 2025 Nov 5:297:117945. doi: 10.1016/j.ejmech.2025.117945.
Dong Luo 1,  Maojie Zhang 2,  Zizhen Liang 1,  Linling Gan 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 Zunyi Medical and Pharmaceutical College, Zunyi, 563006, PR China.
  • 3 Chongqing Engineering Research Center of Pharmaceutical Sciences, School of Pharmacy, Chongqing Medical and Pharmaceutical College, Chongqing, 401331, PR China. Electronic address: ganlinling2012@163.com.
  • 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: 40633334 DOI: 10.1016/j.ejmech.2025.117945
Abstract

Mutations in isocitrate dehydrogenases (IDHs) are frequently observed in various malignancies. These mutations confer a neomorphic enzymatic activity, leading to the reduction of α-KG to the oncometabolite 2-HG. The aberrant accumulation of 2-HG inhibits α-KG-dependent histone and DNA demethylases, thus contributing to tumorigenesis. Consequently, considerable efforts have been directed toward the development of selective inhibitors targeting mutant IDHs. Herein, we report a high-throughput virtual screening campaign utilizing a chemical library of 1795658 compounds, which led to the identification of a promising IDH1 R132H inhibitor. Subsequent structure-based optimization yielded compounds 13e and 16a, which displayed potent inhibition of IDH1 R132H (IC50 = 0.26 and 0.22 μM) and IDH1 R132C (IC50 = 1.1 and 0.93 μM), while showing negligible activity against wt-IDH1 and wt-IDH2. Furthermore, both compounds effectively suppressed intracellular 2-HG production in U87-MG R132H cells (EC50 = 0.55 and 1.45 μM). Additionally, 13e and 16a exhibited moderate antiproliferative effects against U87-MG R132H and HT-1080 cells, while exhibiting low cytotoxicity toward normal human cells even at concentrations up to 40 μM.

Keywords

Isocitrate dehydrogenases 1; Structure-activity relationship study; Structure-based virtual screening.

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