Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms

Abstract

Because the overexpression of histone deacetylase enzymes (HDACs) has been linked to numerous diseases, including various cancers and neurodegenerative disorders, HDAC inhibitors have emerged as promising therapeutic agents. However, most HDAC inhibitors lack both subclass and isoform selectivity, which leads to potential toxicity. Unlike classical hydroxamate HDAC inhibitors, slow-binding HDAC inhibitors form tight and prolonged bonds with HDAC enzymes. This distinct mechanism of action improves both selectivity and toxicity profiles, which makes slow-binding HDAC inhibitors a promising class of therapeutic agents for various diseases. Therefore, the development of slow-binding HDAC inhibitors that can effectively target a wide range of HDAC isoforms is crucial. This Perspective provides valuable insights into the potential and progress of slowbinding HDAC inhibitors as promising drug candidates for the treatment of various diseases. ■ SIGNIFICANCE • Drugs with longer residence times exhibit enhanced and sustained in vivo activity within animal models, potentially serving as an indicator of the drug's effectiveness. • This Perspective focuses on the recent development of slow-binding inhibitors designed to target specific HDAC isoforms through a critical understanding of the existing approaches. • It accentuates limitations and explores potential future directions within the field of HDAC inhibitor development, fostering a deeper comprehension of multifaceted issues through a scientifically driven narrative.

Hydrazides as Inhibitors of Histone Deacetylases

“…However, its binding kinetic had not been investigated until recently when Moreno-Yruela and Olsen conducted a detailed analysis . They discovered that compound 2 is a slow-binding inhibitor, a relatively new concept currently under investigation …”