IDH抑制剂的现状:新出现的问题和观点。

IF 3 4区 医学 Q3 CHEMISTRY, MEDICINAL
João A L de Lima, Lídia Moreira Lima
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引用次数: 0

摘要

异柠檬酸脱氢酶(IDH)是细胞代谢必不可少的酶,包括克雷布斯循环、谷氨酰胺代谢、脂肪生成和氧化还原平衡。IDH1和IDH2的突变与胶质瘤、急性髓性白血病(AML)、胆管癌等多种肿瘤有关,它们会改变酶的活性并导致2-羟戊二酸(2-HG)的过量产生。这种肿瘤代谢物破坏α- kg依赖蛋白,损害分化、分裂和DNA修复等关键过程。对这些遗传、生化和临床方面的了解使得IDH酶成为有希望的治疗靶点,促进了针对含有IDH1或IDH2点突变的肿瘤的靶向抑制剂的开发。选择性抑制剂如ivosidenib (AG-120)和enasidenib (AG-221),分别靶向突变体IDH1和IDH2,阻断2- HG的产生并诱导分化,获得临床成功-特别是在AML中。然而,继发性突变引起的耐药,特别是在变构结合位点,仍然是一个主要障碍。为此,出现了新的方法,如共价抑制剂LY3410738,它可以不可逆地结合突变残基,以及双重抑制剂vorasidenib (AG-881),它可以同时作用于IDH1和IDH2突变,并穿透血脑屏障治疗实体肿瘤。然而,许多临床因素必须考虑。本综述探讨了idh靶向治疗的现状,强调了对新型抑制剂的需求和创新策略,包括设计更小、更有效的分子,具有良好的药代动力学和药物重新定位的潜力。我们强调,发现针对IDH的新型抗肿瘤化合物需要跨生物医学领域的合作努力。这些进展旨在克服耐药性,扩大治疗选择,并提高idh靶向治疗的有效性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
State of the Art of IDH Inhibitors: Emerging Questions and Perspectives.

Isocitrate Dehydrogenases (IDH) are ubiquitous enzymes essential for cellular metabolism, including the Krebs cycle, glutamine metabolism, lipogenesis, and redox balance. Mutations in IDH1 and IDH2 are implicated in several tumors - gliomas, Acute Myeloid Leukemia (AML), cholangiocarcinoma - altering enzyme activity and causing the overproduction of 2-hydroxyglutarate (2-HG). This oncometabolite disrupts α-KGdependent proteins, impairing key processes such as differentiation, division, and DNA repair. Understanding these genetic, biochemical, and clinical aspects has made IDH enzymes promising therapeutic targets, prompting the development of targeted inhibitors for tumors harboring IDH1 or IDH2 point mutations. Selective inhibitors like ivosidenib (AG-120) and enasidenib (AG-221), targeting mutant IDH1 and IDH2 respectively, block 2- HG production and induce differentiation, achieving clinical success - particularly in AML. However, resistance due to secondary mutations, especially in the allosteric binding site, remains a major obstacle. In response, novel approaches have emerged, such as covalent inhibitors like LY3410738, which irreversibly bind mutant residues, and dual inhibitors like vorasidenib (AG-881), which act on both IDH1 and IDH2 mutations and penetrate the blood-brain barrier for treating solid tumors. Still, many clinical factors must be considered. This review explores the current landscape of IDH-targeted therapies, emphasizing the need for novel inhibitors and highlighting innovative strategies, including the design of smaller, more potent molecules with favorable pharmacokinetics and the potential of drug repositioning. We underscore that discovering new antitumor compounds targeting IDH requires a collaborative effort across biomedical fields. These advancements aim to overcome resistance, broaden therapeutic options, and improve the effectiveness of IDH-targeted treatments.

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来源期刊
Anti-cancer agents in medicinal chemistry
Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL
CiteScore
5.10
自引率
3.60%
发文量
323
审稿时长
4-8 weeks
期刊介绍: Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.
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