Wang Yifan, Bai Hailong, Wang Aixin, Zhao Jun, Guo Hui, Tang Yuping, Wang Yuwei, Xie Qinjian
College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi Province, China.
Gansu Corps Hospital of CAPF, Lanzhou, Gansu, China.
Chem Biol Drug Des. 2025 Apr;105(4):e70102. doi: 10.1111/cbdd.70102.
Isocitrate dehydrogenase 1 (IDH1) is a pivotal enzyme in cellular energy metabolism, playing a crucial role in the conversion of isocitrate into α-ketoglutarate (α-KG). When IDH1 undergoes mutation, it catalyzes the conversion of α-KG into the oncogenic metabolite 2-hydroxyglutarate (2-HG). Subsequently, 2-HG competitively suppresses a range of α-KG-dependent dioxygenase activities, ultimately leading to hypermethylation of DNA or histones, which in turn causes the occurrence of various malignant tumors, including acute myeloid leukemia (AML), glioma, and chondrosarcoma. Currently, the FDA has granted approval for the use of the small molecule inhibitor Ivosidenib (AG-120) in the treatment of IDH1-mutated AML and cholangiocarcinoma. Although AG-120 has benefited patients clinically, drug resistance has gradually emerged and has become a major problem in the treatment of mutant IDH1 (mIDH1) diseases. In this review, we highlighted the function of IDH1 mutations in cancer treatment and described detailed resistance mechanisms in terms of IDH1-specific mutation sites. Representative mIDH1 inhibitors and their binding modes were also discussed. In particular, we summarized seven strategies to overcome drug resistance, which provide a basis for understanding the mechanism of drug resistance for IDH1 mutations and exploring guidance to overcome drug resistance.
异柠檬酸脱氢酶1（IDH1）是细胞能量代谢中的关键酶，在异柠檬酸转化为α-酮戊二酸（α-KG）过程中发挥着至关重要的作用。当IDH1发生突变时，它会催化α-KG转化为致癌代谢物2-羟基戊二酸（2-HG）。随后，2-HG竞争性抑制一系列α-KG依赖性双加氧酶活性，最终导致DNA或组蛋白的高甲基化，进而引发包括急性髓系白血病（AML）、胶质瘤和软骨肉瘤在内的各种恶性肿瘤的发生。目前，美国食品药品监督管理局（FDA）已批准使用小分子抑制剂艾伏尼布（AG-120）治疗IDH1突变的AML和胆管癌。尽管AG-120在临床上使患者受益，但耐药性已逐渐出现，并已成为治疗突变型IDH1（mIDH1）疾病的主要问题。在本综述中，我们强调了IDH1突变在癌症治疗中的作用，并根据IDH1特异性突变位点描述了详细的耐药机制。还讨论了代表性的mIDH1抑制剂及其结合模式。特别是，我们总结了七种克服耐药性的策略，为理解IDH1突变的耐药机制和探索克服耐药性的指导提供了依据。
