Selective HAT Inhibitors as Mechanistic Tools for Protein Acetylation

Selective and potent bisubstrate analog inhibitors are now available for the PCAF/GCN5 and p300/CBP enzymes. The development of these inhibitors has provided for new insights into the mechanisms of histone acetyltransferases and the role of protein acetylation in gene regulation. They have been particularly powerful in dissecting the role of p300/CBP HAT activity in the context of its overall contributions to gene regulation. Despite their utility, several challenges still exist. No potent HAT inhibitors have been reported for the EsaI family of HATs and no compounds can distinguish between the close homologs p300 and CBP or PCAF and GCN5. Moreover, increasing the cell permeability properties of existing compounds is an important future direction. Ultimately, it will be of great importance to know whether small molecule HAT inhibitors can make an impact on the treatment of human disease.