In this perspective, we discuss the emerging class of epigenetic cancer therapies targeting acetylrecognition domain–containing factors. These chromatin-associated factors bind to or ‘recognize’ histone lysine acetylation, a type of epigenetic modification associated with active transcription. Histones are protein subunits which together form an octamer core around which 146–147 bp of DNA is wound to form a nucleosome, the basic unit of chromatin organization. Histone acetyltransferase (HAT) enzymes acetylate specific lysine residues within the both the globular core and unstructured tails of histone proteins H2A, H2B, H3, and H4. By neutralizing the positive charge on histone lysine residues, acetylation relaxes the binding interaction between histone octamers and negatively charged DNA within and between nucleosomes, increasing the accessibility of chromatin to transcriptional machinery. Histone acetylation can therefore be thought of as a transcriptional ‘on switch’ due to its direct, physical impact on chromatin accessibility. However, because histone acetylation can be bound by chromatin-associated factors with appropriate domains, it can also be thought of as a recognizable ‘on signal’ that initiates the recruitment of effectors to drive transcriptional activation. Additionally, because acetylrecognition domain–containing factors can selectively bind to acetylation at specific lysine positions, or even to specific combinations of histone acetylation and methylation marks, histone acetylation has also been conceptualized as part of a ‘readable’ ‘histone code’ [1].

We will discuss relevant results of recent clinical studies, placing the clinical performance of therapies targeting acetylrecognition domain–containing factors within a broader context of preclinical evidence and ongoing research in cancer and epigenetics. Based on their progress into clinical stages of therapeutic development, we first discuss inhibitors targeting the bromodomains of BRD4 and other bromodomain and extraterminal domain (BET) family proteins. Because these pan-BET inhibitors (BETi) have been largely underwhelming in clinical trials, we will present a perspective on therapeutic targeting of BRD4-PTEFb informed by recent results from our group, discussing existing and potential alternatives. We will also discuss inhibitors recently developed to target the bromodomains and other acetylrecognition domains (PHD, YEATS) of important epigenetic and transcriptional regulatory factors, as well as proximity-based therapies (e.g. proteolysis-targeting chimeras [PROTACs]) developed to target some of these for proteasomal degradation. After discussing recent studies that expand our understanding of the selectivity and combinatorial specificity of acetylrecognition domains, we will conclude with opinion on how to best approach the emerging class of therapies targeting acetylrecognition domain–containing factors to more effectively target epigenetic and transcriptional regulatory mechanisms in the treatment of cancer. .