异柠檬酸脱氢酶1突变体抑制剂的发现、合成与抗肿瘤活性研究

Isocitrate dehydrogenase 1 (IDH1) is a key enzyme involved in cellular energy metabolism. Under normal conditions, IDH1 catalyzes oxidative decarboxylation of isocitrate to generate α-ketoglutaric acid. It was found that IDH1 is frequently mutated in a variety of malignant tumors, and the mutants reduce α-ketoglutarate to the onco-metabolite 2-HG, which leads to tumorigenesis and development. Therefore, targeting IDH1 mutants (mIDH1) to develop inhibitors to reduce 2-HG concentration in tumor cells is an effective approach for tumor therapy. In this paper, we identified 15 potential compounds that can form hydrogen bond interactions with key amino acid residues in mIDH1 through high-throughput virtual screening, which were subsequently synthzied and evaluated for IDH1 R132H inhibitory activity, and the results suggested that compound 21 has excellent inhibitory activity and is deservedfor further evaluation.