The Allosteric Regulator Inositol Phosphate Dramatically Affects the Efficacy and Selectivity of Inhibitors for Different HDAC Complexes

Class I histone deacetylases regulate gene transcription and are established therapeutic targets. HDAC1-3 form the catalytic subunit in several distinct multiprotein complexes; however, HDAC inhibitors are rarely studied in the context of these complexes. We evaluated multiple inhibitors, using seven HDAC complexes, and found that the inhibition profiles were highly complex-dependent, despite targeting the same enzyme. We also investigated the effect of the allosteric regulator inositol phosphate on these inhibitors. We observed very large, complex-selective reductions in the potency of benzamides bearing a "foot-pocket group", proposed to be selective for HDAC1/2. The potencies of these compounds are likely to be profoundly different <i>in vivo</i> compared with <i>in vitro</i> potencies in the absence of inositol phosphates. Our findings are supported by cell-based assays evaluating histone acetylation and HDAC degradation, highlighting the importance of evaluating HDACi in the context of HDAC complexes and inositol phosphates.