Expanding the HDAC druggable landscape beyond enzymatic inhibition

Enzymatic pockets such as those of histone deacetylases (HDACs) are among the most favored targets for drug development. However, enzymatic inhibitors often exhibit low selectivity and high toxicity due to the existence of multiple enzyme paralogs, each acting in the context of many distinct multisubunit complexes. Here, we expand the HDAC druggable space beyond enzymatic inhibition by targeting transcriptional repression functions of a whole HDAC complex in vivo. Among the non-enzymatic inhibitors identified, one targets the conserved SIN3 subunit, disrupting its interaction with a DNA-binding protein and recruitment of the complex to specific genes. While conferring phenotypes on par with those of HDAC enzymatic inhibitors, this molecule leads to more selective transcriptomic changes in disease models, affecting expression of up to 100-fold fewer genes. Thus, our results demonstrate that highly selective epigenetic modulators can be identified beyond those affecting enzymatic activity, with the potential of developing therapeutics with decreased toxicity.