Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139; email:
Annu Rev Biochem. 2017 Jun 20;86:305-331. doi: 10.1146/annurev-biochem-061516-044732. Epub 2017 Apr 3.
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.
在包括继发性胶质母细胞瘤、急性髓性白血病、肝内胆管细胞癌和软骨肉瘤等多种癌症中，代谢酶异柠檬酸脱氢酶（IDH）的杂合突变的鉴定，促使人们开展了大量的发现工作，以阐明这些突变在致癌作用中的参与，并开发治疗方法。我们在此对这些研究进行了综述。三种 IDH 同工酶（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）有助于调节中央代谢的电路。一些生化和遗传观察导致了突变 IDH1 和 IDH2（mIDH）产生致癌代谢物（R）-2-羟戊二酸（2-HG）的新表型的发现。IDH1/2 的杂合突变和 2-HG 的积累导致深刻的代谢和表观遗传失调，包括抑制正常的细胞分化，导致疾病。在针对 mIDH 的化合物的开发过程中进行的晶体结构研究表明，不同的化学型具有共同的变构抑制作用。正在进行的针对 mIDH 高级血液恶性肿瘤患者的临床试验，提供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。
