Proximity-based Therapeutic Modalities for Precise Modulation of Histone Deacetylases

Abstract

Histone deacetylases (HDACs) serve as critical epigenetic regulators that modulate gene expression through catalytic removal of acetyl groups from histone substrates. By controlling the acetylation status of both histone and non-histone proteins, HDACs orchestrate fundamental cellular processes including cell cycle, chromatin decondensation, apoptosis and angiogenesis. These pleiotropic functions have established HDACs as validated therapeutic targets in oncology, evidenced by the FDA and CFDA approval of five HDAC inhibitors for various cancer indications to date. <br/> Despite their clinical utility, currently available HDAC inhibitors suffer from significant off-target effects, including nausea, vomiting, fatigue, and cardiotoxicity, that largely result from their pan-HDAC inhibitory activity across multiple isoforms. Developing isoform-selective HDAC modulators represents a promising strategy to overcome these limitations, as targeted pharmacological regulation of specific HDAC family members could potentially maintain therapeutic efficacy while substantially reducing adverse effects. <br/> To address these limitations, three innovative proximity-based therapeutic modalities were designed to achieve precise control of HDAC activity. These approaches leverage targeted protein modulation to enhance isoform specificity while minimizing off-target effects, potentially overcoming the key challenges that have constrained the clinical utility of conventional HDAC inhibitors in oncology applications.