Comprehensive Exploration of Isocitrate Dehydrogenase (IDH) Mutations: Tumorigenesis, Drug Discovery, and Covalent Inhibitor Advances

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-11-15 DOI:10.1016/j.ejmech.2024.117041

Conghao Gai, Hairong Zeng, Haoming Xu, Xiaoyun Chai, Yan Zou, Chunlin Zhuang, Guangbo Ge, Qingjie Zhao

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Abstract

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.

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全面探索异柠檬酸脱氢酶 (IDH) 突变：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，它能产生α-酮戊二酸（α-KG）。然而，IDH 突变体可进一步将 α-KG 还原成 2-羟基戊二酸（2-HG），而 2-HG可竞争性地抑制依赖于 α-KG 的酶，从而导致正常羟化途径的下调。良好的 IDH 突变体抑制剂能有效降低 2-HG 的水平，从而干扰细胞的恶性转化。在这篇综述中，我们介绍了IDH的生物学功能，描述了IDH变体的肿瘤发生机制，并回顾了2012-2024年间基于结构的临床抑制剂的药物发现。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，这些方法可帮助研究人员快速构建药物发现和开发的工作流程。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.