慢结合和共价 HDAC 抑制:新范例?

IF 8.5 Q1 CHEMISTRY, MULTIDISCIPLINARY JACS Au Pub Date : 2024-10-31 DOI:10.1021/jacsau.4c0082810.1021/jacsau.4c00828
Yasir S. Raouf*,  and , Carlos Moreno-Yruela*, 
{"title":"慢结合和共价 HDAC 抑制:新范例?","authors":"Yasir S. Raouf*,&nbsp; and ,&nbsp;Carlos Moreno-Yruela*,&nbsp;","doi":"10.1021/jacsau.4c0082810.1021/jacsau.4c00828","DOIUrl":null,"url":null,"abstract":"<p >The dysregulated post-translational modification of proteins is an established hallmark of human disease. Through Zn<sup>2+</sup>-dependent hydrolysis of acyl-lysine modifications, histone deacetylases (HDACs) are key regulators of disease-implicated signaling pathways and tractable drug targets in the clinic. Early targeting of this family of 11 enzymes (HDAC1–11) afforded a first generation of broadly acting inhibitors with medicinal applications in oncology, specifically in cutaneous and peripheral T-cell lymphomas and in multiple myeloma. However, first-generation HDAC inhibitors are often associated with weak-to-modest patient benefits, dose-limited efficacies, pharmacokinetic liabilities, and recurring clinical toxicities. Alternative inhibitor design to target single enzymes and avoid toxic Zn<sup>2+</sup>-binding moieties have not overcome these limitations. Instead, recent literature has seen a shift toward noncanonical mechanistic approaches focused on slow-binding and covalent inhibition. Such compounds hold the potential of improving the pharmacokinetic and pharmacodynamic profiles of HDAC inhibitors through the extension of the drug–target residence time. This perspective aims to capture this emerging paradigm and discuss its potential to improve the preclinical/clinical outlook of HDAC inhibitors in the coming years.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4148–4161 4148–4161"},"PeriodicalIF":8.5000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00828","citationCount":"0","resultStr":"{\"title\":\"Slow-Binding and Covalent HDAC Inhibition: A New Paradigm?\",\"authors\":\"Yasir S. Raouf*,&nbsp; and ,&nbsp;Carlos Moreno-Yruela*,&nbsp;\",\"doi\":\"10.1021/jacsau.4c0082810.1021/jacsau.4c00828\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The dysregulated post-translational modification of proteins is an established hallmark of human disease. Through Zn<sup>2+</sup>-dependent hydrolysis of acyl-lysine modifications, histone deacetylases (HDACs) are key regulators of disease-implicated signaling pathways and tractable drug targets in the clinic. Early targeting of this family of 11 enzymes (HDAC1–11) afforded a first generation of broadly acting inhibitors with medicinal applications in oncology, specifically in cutaneous and peripheral T-cell lymphomas and in multiple myeloma. However, first-generation HDAC inhibitors are often associated with weak-to-modest patient benefits, dose-limited efficacies, pharmacokinetic liabilities, and recurring clinical toxicities. Alternative inhibitor design to target single enzymes and avoid toxic Zn<sup>2+</sup>-binding moieties have not overcome these limitations. Instead, recent literature has seen a shift toward noncanonical mechanistic approaches focused on slow-binding and covalent inhibition. Such compounds hold the potential of improving the pharmacokinetic and pharmacodynamic profiles of HDAC inhibitors through the extension of the drug–target residence time. This perspective aims to capture this emerging paradigm and discuss its potential to improve the preclinical/clinical outlook of HDAC inhibitors in the coming years.</p>\",\"PeriodicalId\":94060,\"journal\":{\"name\":\"JACS Au\",\"volume\":\"4 11\",\"pages\":\"4148–4161 4148–4161\"},\"PeriodicalIF\":8.5000,\"publicationDate\":\"2024-10-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00828\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JACS Au\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/jacsau.4c00828\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JACS Au","FirstCategoryId":"1085","ListUrlMain":"https://pubs.acs.org/doi/10.1021/jacsau.4c00828","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

摘要

蛋白质翻译后修饰失调是人类疾病的既定特征。通过 Zn2+ 依赖性水解酰基赖氨酸修饰,组蛋白去乙酰化酶(HDACs)是影响疾病的信号通路的关键调节因子,也是临床上可行的药物靶点。早期以这个由 11 种酶组成的家族(HDAC1-11)为靶点,开发出了第一代作用广泛的抑制剂,并将其应用于肿瘤学领域,特别是皮肤淋巴瘤、外周 T 细胞淋巴瘤和多发性骨髓瘤。然而,第一代 HDAC 抑制剂对患者的益处往往微乎其微、疗效受剂量限制、药代动力学缺陷以及反复出现的临床毒性。针对单一酶和避免有毒 Zn2+ 结合分子的替代抑制剂设计并没有克服这些局限性。相反,最近的文献显示,人们开始转向非经典的机理方法,侧重于缓慢结合和共价抑制。通过延长药物在靶点的停留时间,此类化合物有望改善 HDAC 抑制剂的药代动力学和药效学特征。本视角旨在捕捉这一新兴范例,并讨论其在未来几年改善 HDAC 抑制剂临床前/临床前景的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Slow-Binding and Covalent HDAC Inhibition: A New Paradigm?

The dysregulated post-translational modification of proteins is an established hallmark of human disease. Through Zn2+-dependent hydrolysis of acyl-lysine modifications, histone deacetylases (HDACs) are key regulators of disease-implicated signaling pathways and tractable drug targets in the clinic. Early targeting of this family of 11 enzymes (HDAC1–11) afforded a first generation of broadly acting inhibitors with medicinal applications in oncology, specifically in cutaneous and peripheral T-cell lymphomas and in multiple myeloma. However, first-generation HDAC inhibitors are often associated with weak-to-modest patient benefits, dose-limited efficacies, pharmacokinetic liabilities, and recurring clinical toxicities. Alternative inhibitor design to target single enzymes and avoid toxic Zn2+-binding moieties have not overcome these limitations. Instead, recent literature has seen a shift toward noncanonical mechanistic approaches focused on slow-binding and covalent inhibition. Such compounds hold the potential of improving the pharmacokinetic and pharmacodynamic profiles of HDAC inhibitors through the extension of the drug–target residence time. This perspective aims to capture this emerging paradigm and discuss its potential to improve the preclinical/clinical outlook of HDAC inhibitors in the coming years.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
9.10
自引率
0.00%
发文量
0
审稿时长
10 weeks
期刊最新文献
Issue Editorial Masthead Issue Publication Information Revealing the Ultrafast Energy Transfer Pathways in Energetic Materials: Time-Dependent and Quantum State-Resolved Mechanistic Insights into Nonadiabatic Interband Transitions on a Semiconductor Surface Induced by Hydrogen Atom Collisions Sequence-Encoded Spatiotemporal Dependence of Viscoelasticity of Protein Condensates Using Computational Microrheology
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1