Recent advances in the development of histone deacylase SIRT2 inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Sirtuin 2 (SIRT2) is an atypical histone deacetylase with diverse regulatory roles.
• SIRT2 activity is implicated in diseases including cancers and Parkinson's disease.
• Dysregulated SIRT2 presents a therapeutic target for various disorders.

Purpose of the Study:

• To systematically review small-molecule inhibitors of Sirtuin 2 (SIRT2).
• To detail the discovery and structural optimization strategies for SIRT2 inhibitors.
• To provide insights for developing novel SIRT2-targeting therapeutics.

Main Methods:

• Literature review of scientific publications.
• Systematic summary of nine distinct chemotypes of small-molecule SIRT2 inhibitors.
• Analysis of structure-activity relationships and optimization approaches.

Main Results:

• Identification and categorization of nine chemotypes of SIRT2 inhibitors.
• Detailed description of inhibitor discovery pathways.
• Elucidation of structural optimization strategies for enhanced potency and selectivity.

Conclusions:

• SIRT2 is a crucial therapeutic target due to its role in disease pathogenesis.
• Small-molecule inhibitors offer promising avenues for SIRT2-targeted therapies.
• This review provides a foundation for future drug discovery efforts against SIRT2.