脑胶质瘤中异柠檬酸脱氢酶突变及其抑制剂研究进展

Current Progress in Isocitrate Dehydrogenase Mutations and Its Inhibitors in Gliomas

异柠檬酸脱氢酶突变存在于多数脑胶质瘤中,这是一种新的点突变,可导致原有的酶活性丧失,但却能催化α-酮戊二酸生成具有致癌作用的R-2-羟基戊二酸。异柠檬酸脱氢酶抑制剂能够减少R-2-羟基戊二酸的产生,诱导组蛋白去甲基化,从而抑制肿瘤发展。从2012年,首个抑制剂被发现,异柠檬酸脱氢酶突变体抑制剂就成为脑胶质瘤治疗领域的研究重点。2017年8月和2018年7月,异柠檬酸脱氢酶2突变体抑制剂enasidenib(AG-221)和异柠檬酸脱氢酶1突变体抑制剂ivosidenib(AG-120)相继被FDA批准上市,用于急性髓细胞性白血病的治疗,证实了异柠檬酸脱氢酶突变体作为肿瘤治疗靶点的可靠性。目前全球多个医药机构都在进行异柠檬酸脱氢酶抑制剂的研发,笔者对现有异柠檬酸脱氢酶抑制剂的研究现状进行综述。

Glioma is a primary brain tumor produced by canceration of the glial cells in the brain and spinal cord,accounting for74. 6% of the malignant tumors in the central nervous system. Isocitrate dehydrogenase( IDH) is the rate-limiting enzyme of the tricarboxylic acid cycle and catalyzes the oxidative decarboxylation of isocitrate to produce α-ketoglutarate( α-KG). Its mutant( m IDH) is a new point mutation,not only lose its original function but also gain new activity: catalyzing the production of carcinogenic R-2-hydroxyglutarate( 2 HG) by α-KG. Isocitrate dehydrogenase inhibitors can reduce the production of 2 HG and induce the demethylation of histones,thereby inhibiting tumor progression. Although discovered in 2008,the m IDH has become a tumor diagnostic marker and therapeutic target,m IDH2 and m IDH1 inhibitors for acute myeloid leukemia have been approved for marketing in 2017 and 2018,respectively. For the treatment of acute myeloid leukemia,the reliability of isocitrate dehydrogenase mutants as tumor therapeutic targets was confirmed. At present,many pharmaceutical institutions around the world are conducting research and development of isocitrate dehydrogenase inhibitors. This article reviews the current research status of current IDH inhibitors.