Isocitrate dehydrogenase (IDH) is an enzyme that catalyses the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (α-KG) relative to the hydroxylation of substrates. However, IDH mutants can further reduce α-KG to 2-hydroxyglutarate (2-HG) which competitively inhibits α-KG dependent enzymes, leading to the downregulation of normal hydroxylation pathways. Good IDH mutant inhibitors can effectively reduce the level of 2-HG and therefore disturb cellular malignant transformation. In this review, we introduce the biological functions of IDH, describe the tumorigenesis mechanisms of IDH variants, and review the structure-based drug discovery of clinical inhibitors during 2012-2024. We also find successful applications of covalent strategy in the development of irreversible IDH inhibitors. Biological screening methods are also collected in this paper, which may help researchers to rapidly construct workflows for drug discovery and development.

中文翻译：

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异柠檬酸脱氢酶 （IDH） 突变的全面探索：肿瘤发生、药物发现和共价抑制剂的进展


异柠檬酸脱氢酶 （IDH） 是一种催化异柠檬酸氧化脱羧的酶，相对于底物的羟基化产生 α-酮戊二酸 （α-KG）。然而，IDH 突变体可以进一步将 α-KG 还原为 2-羟基戊二酸 （2-HG），后者竞争性地抑制 α-KG 依赖性酶，导致正常羟基化途径的下调。良好的 IDH 突变抑制剂可有效降低 2-HG 水平，从而干扰细胞恶性转化。本文介绍了 IDH 的生物学功能，描述了 IDH 变异的肿瘤发生机制，并回顾了 2012-2024 年临床抑制剂基于结构的药物发现。我们还发现了共价策略在不可逆 IDH 抑制剂开发中的成功应用。本文还收集了生物筛选方法，这可能有助于研究人员快速构建药物发现和开发的工作流程。