Experimental approaches toward histone acetyltransferase modulators as therapeutics

Histone acetyltransferases (HATs) are essential enzymes that are, among others, involved in the epigenetic regulation of gene transcription. They exert their functions through acetylation of both histone and nonhistone proteins and are often part of multiprotein complexes. This chapter mainly discusses recent studies on the functions of HATs in diseases and their utility as potential drug targets. Furthermore, this chapter describes the recent progress in the development of small-molecule HAT modulators and their therapeutic potential. Dysregulation of HAT-mediated acetylation of histone and nonhistone proteins contributes to the pathogenesis and progression of many diseases, such as cancers, inflammatory diseases, and neurological disorders. In recent years, a variety of HAT modulators has been developed, including inhibitors and activators of HAT catalytic activity. Furthermore, inhibitors of HAT protein-protein interactions were developed such as inhibitors of HAT bromodomains. An interesting novel development in HAT-directed drug discovery is the development of proteolysis-targeting chimeras (PROTACs) that trigger proteasome-mediated degradation of HAT proteins. Taken together, these studies demonstrate that HAT proteins are versatile and promising targets for drug discovery.