Overview of class I HDAC modulators: Inhibitors and degraders

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Class I histone deacetylases (HDACs) play critical roles in diseases like cancer.
• Conventional HDAC inhibitors face challenges including resistance, toxicity, and limited efficacy.
• New therapeutic strategies are needed to effectively target Class I HDACs.

Purpose of the Study:

• To provide a comprehensive overview of Class I HDAC enzymes and inhibitors.
• To review recent advancements in Class I HDAC modulators for cancer therapeutics.
• To discuss challenges and future prospects in Class I HDAC-targeted drug discovery.

Main Methods:

• Literature review of Class I HDAC enzymes and inhibitors.
• Analysis of recent advancements in dual-acting inhibitors, targeted protein degradation (TPD) technologies (PROTACs, molecular glues, HyT degraders), and covalent inhibitors.
• Examination of rational design principles, pharmacodynamics, pharmacokinetics, and clinical progress.

Main Results:

• Class I HDACs are key targets in cancer drug development.
• Novel strategies like dual-acting inhibitors and TPDs show promise in overcoming limitations of conventional inhibitors.
• Isoform-selective inhibitors, dual-target inhibitors, TPDs, and covalent inhibitors represent significant progress.

Conclusions:

• Advancements in Class I HDAC modulators offer new avenues for cancer treatment.
• Targeted protein degradation and dual-acting inhibitors are promising strategies.
• Further research is needed to address challenges and optimize clinical application of these novel agents.