摘要
异柠檬酸脱氢酶家族(isocitrate dehydrogenase,IDHs)是参与三羧酸循环的关键代谢酶,可催化异柠檬酸氧化脱羧为2-氧戊二酸(2-OG)。IDH家族包含三种同工酶(IDH1、IDH2和IDH3),其中IDH1存在于细胞质和过氧化物酶体,而IDH2和IDH3则定位于线粒体中。在胶质瘤、AML、胆管癌、软骨肉瘤、肺癌等多种人类疾病中,存在IDH1催化位点关键精氨酸突变(R132H、R132C、R132L和R132S),其中R132H与R132C最为广泛。这些突变酶获得了新形态活性:将2-OG进一步还原为D-2-羟基戊二酸(D-2-HG),进而导致IDH1突变细胞中D-2-HG的含量大量积累,而D-2-HG是一种致癌代谢物,能促进肿瘤的发生与发展。目前,突变异柠檬酸脱氢酶1(m IDH1)已经成为一个很有潜力的治疗靶点,但大多数m IDH1抑制剂仍然处于临床试验阶段,只有AG-120(Ivosidenib)被FDA批准上市,用于治疗复发性/难治性急性髓系白血病。该综述重点讨论IDH1突变酶的潜在抑制剂及其在恶性肿瘤中的研究进展,为开展m IDH1抑制剂研究工作提供参考。
Isocitrate dehydrogenase(IDHs) is a key metabolic enzyme involved in the tricarboxylic acid cycle, which can catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate(2-OG). The IDH family contains three isozymes(IDH1, IDH2 and IDH3). IDH1 is located in the cytoplasm, and IDH2 and IDH3 are presented in the mitochondria. There are key arginine mutations(R132 H, R132 C, R132 L and R132 S) in the catalytic site of IDH1 in a variety of human diseases such as glioma, AML, cholangiocarcinoma, chondrosarcoma and lung cancer, while R132 H and R132 C are the most abundant. IDH1 mutants acquired a new morphological activity that further reduced 2-OG to D-2-hydroxyglutaric acid(D-2-HG), while the large amount of D-2-HG accumulated in IDH1 mutant cells can promote the occurrence and development of tumours. At present, mutant IDH1 enzymes have become a promising therapeutic target, Only AG-120(Ivosidenib) has been approved by the FDA for the treatment of relapsed/refractory acute myeloid leukemia. In this review, we focus on discussing potential inhibitors of IDH1 mutant enzymes and their research progress in malignant tumours, providing a basis for better research on m IDH1 inhibitors.
作者
王莹莹
查晓明
Wang Yingying;Zha Xiaoming(School of Engineering,China Pharmaceutical University,Nanjing 211198,China)
出处
《广东化工》
CAS
2021年第15期130-131,141,共3页
Guangdong Chemical Industry
