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Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development
Annual Review of Biochemistry ( IF 16.6 ) Pub Date : 2017-06-27 00:00:00 , DOI: 10.1146/annurev-biochem-061516-044732
Lenny Dang 1 , Shin-San Michael Su 1
Affiliation  

The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations’ involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms (nicotinamide adenine dinucleotide phosphate–dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide–dependent IDH3) contribute to regulating the circuitry of central metabolism. Several biochemical and genetic observations led to the discovery of the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) by mutant IDH1 and IDH2 (mIDH). Heterozygous mutation of IDH1/2 and accumulation of 2-HG cause profound metabolic and epigenetic dysregulation, including inhibition of normal cellular differentiation, leading to disease. Crystallographic structural studies during the development of compounds targeting mIDH demonstrated common allosteric inhibition by distinct chemotypes. Ongoing clinical trials in patients with mIDH advanced hematologic malignancies have demonstrated compelling clinical proof-of-concept, validating the biology and drug discovery approach.

中文翻译:


异柠檬酸脱氢酶突变和 (R)-2-羟基戊二酸:从基本发现到治疗开发

在癌症亚群(包括继发性胶质母细胞瘤、急性髓细胞性白血病、肝内胆管癌和软骨肉瘤)中识别出代谢酶异柠檬酸脱氢酶 (IDH) 的杂合突变,导致发现这些突变参与癌变和开发治疗方法的努力,我们在这里回顾。三种 IDH 亚型(烟酰胺腺嘌呤二核苷酸磷酸依赖性 IDH1 和 IDH2,以及烟酰胺腺嘌呤二核苷酸依赖性 IDH3)有助于调节中枢代谢回路。几项生化和遗传观察导致发现了新形态的致癌代谢物(R)-2-羟基戊二酸 (2-HG) 通过突变 IDH1 和 IDH2 (mIDH)。IDH1/2 的杂合突变和 2-HG 的积累导致严重的代谢和表观遗传失调,包括抑制正常细胞分化,从而导致疾病。在针对 mIDH 的化合物开发过程中的晶体结构研究证明了不同化学型的常见变构抑制。正在进行的 mIDH 晚期血液系统恶性肿瘤患者的临床试验已经证明了令人信服的临床概念验证,验证了生物学和药物发现方法。

更新日期:2017-06-27
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