Overview of class I HDAC modulators: Inhibitors and degraders

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.