Chapter 9: Chemical Targeting of Histone Acetyltransferases

Histone acetyltransferases (HATs) are a class of enzymes that catalyze acetylation of the amino group on the lysine side chains of histones via their HAT domains. Acetylated lysine residues on histones are often associated with chromatin that is accessible to transcription factors and transcriptionally active loci. Given that transcription is often dysregulated in human diseases, particularly in cancers, HATs represent attractive targets for inhibitor and drug development. Many HAT domain-containing proteins are multi-domain proteins with functions extending beyond histone acetylation. Therefore, chemical strategies to inhibit their activity include targeting the HAT domain directly, targeting protein–protein interactions (PPIs) that regulate HAT activity, and targeting the whole protein for degradation as a means of inhibiting HAT activity, disrupting PPIs, and eliminating any other functions. All of these strategies are in current development and have yielded a variety of inhibitors and degraders that are used for mechanistic studies and, more recently, human clinical investigation. With the rapid development of chemical methods to target HAT proteins, we expect increasing mechanistic understanding and therapeutic insights into this class of proteins.