{"title":"IDH抑制剂的现状:新出现的问题和观点。","authors":"João A L de Lima, Lídia Moreira Lima","doi":"10.2174/0118715206382095250908095950","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"State of the Art of IDH Inhibitors: Emerging Questions and Perspectives.\",\"authors\":\"João A L de Lima, Lídia Moreira Lima\",\"doi\":\"10.2174/0118715206382095250908095950\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":7934,\"journal\":{\"name\":\"Anti-cancer agents in medicinal chemistry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2025-09-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Anti-cancer agents in medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/0118715206382095250908095950\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Anti-cancer agents in medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0118715206382095250908095950","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
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.
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.