Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Histone deacetylases (HDACs) regulate gene expression and are implicated in numerous diseases.
• Current HDAC inhibitors (HDACis) often use hydroxamate zinc-binding groups (ZBGs), which can cause toxicity and lack specificity.
• Concerns regarding hydroxamate mutagenicity limit their use in chronic non-oncology treatments.

Purpose of the Study:

• To review advancements in non-hydroxamic HDAC inhibitors developed between 2015 and the present.
• To explore alternative ZBGs that maintain potency while improving selectivity and safety profiles.
• To provide a structured overview of novel ZBG classes based on binding modes and structural similarities.

Main Methods:

• Literature review focusing on non-hydroxamic HDAC inhibitors from 2015 to present.
• Analysis of structural information and binding modes of various ZBGs.
• Clustering of ZBGs based on structural similarity for qualitative assessment.

Main Results:

• Development of alternative ZBGs to replace hydroxamates in HDACis.
• Demonstration of high potency and improved selectivity with novel ZBGs.
• Identification of potential for developing safer HDACis for chronic diseases.

Conclusions:

• Non-hydroxamic HDACis represent a promising therapeutic strategy, overcoming limitations of traditional hydroxamate-based inhibitors.
• Alternative ZBGs offer enhanced selectivity and reduced toxicity, expanding therapeutic applications.
• Structural analysis aids in the rational design of next-generation HDAC inhibitors.