I类组蛋白脱乙酰酶(HDAC)与多种疾病的发展密切相关。包括癌症,神经退行性疾病,艾滋病毒,和炎症性疾病。考虑到在肿瘤发生中的重要作用,I类HDAC已成为治疗策略的高度理想目标,特别是在抗癌药物开发领域。然而,传统的I类HDAC抑制剂面临着一些挑战,如获得性抗性,固有的毒性,以及抑制HDAC非酶功能的功效有限。为了解决这些问题,新的策略已经出现,包括I类HDAC双作用抑制剂的开发,靶向蛋白质降解(TPD)技术,如PROTACs,分子胶,和HyT降解器,以及共价抑制剂。这篇综述提供了I类HDAC酶和抑制剂的全面概述,通过最初介绍它们的结构和生物学作用。随后,我们专注于I类HDAC调制器的最新进展,包括同工型选择性I类抑制剂,双靶点抑制剂,TPDs,和共价抑制剂,从合理设计原则的角度来看,药效学,药代动力学,和临床进展。最后,我们还提供了挑战,并概述了I类HDAC靶向癌症治疗药物发现领域的未来前景。
Class I histone deacetylases (HDACs) are closely associated with the development of a diverse array of diseases, including cancer, neurodegenerative disorders, HIV, and inflammatory diseases. Considering the essential roles in tumorigenesis, class I HDACs have emerged as highly desirable targets for therapeutic strategies, particularly in the field of anticancer drug development. However, the conventional class I HDAC inhibitors faced several challenges such as acquired resistance, inherent toxicities, and limited efficacy in inhibiting non-enzymatic functions of HDAC. To address these problems, novel strategies have emerged, including the development of class I HDAC dual-acting inhibitors, targeted protein degradation (TPD) technologies such as PROTACs, molecular glues, and HyT degraders, as well as covalent inhibitors. This review provides a comprehensive overview of class I HDAC enzymes and inhibitors, by initially introducing their structure and biological roles. Subsequently, we focus on the recent advancements of class I HDAC modulators, including isoform-selective class I inhibitors, dual-target inhibitors, TPDs, and covalent inhibitors, from the perspectives of rational design principles, pharmacodynamics, pharmacokinetics, and clinical progress. Finally, we also provide the challenges and outlines future prospects in the realm of class I HDAC-targeted drug discovery for cancer therapeutics.