E1A-associated protein p300 (EP300) (EP300)

E1A-associated protein p300 (EP300) is a large, multidomain transcriptional coactivator that functions as a histone acetyltransferase (HAT), playing a pivotal role in the epigenetic regulation of gene expression [UniProt: P45973]. The p300 bromodomain is a specialized structural motif that recognizes and binds to acetylated lysine residues on histones and non-histone proteins, acting as a reader of the epigenetic code to recruit transcriptional machinery [PubMed: 27105300]. In various malignancies, including prostate cancer and acute myeloid leukemia, p300 is often co-opted to drive the expression of key oncogenic drivers like MYC and the androgen receptor [PubMed: 31235518]. Small-molecule inhibitors targeting the p300 bromodomain, such as inobrodib (CCS1477), are designed to displace p300 from chromatin, thereby downregulating these oncogenic programs [ClinicalTrials.gov: NCT03568331]. While these inhibitors show significant therapeutic potential, the high degree of homology between p300 and its paralog CBP (CREB-binding protein) necessitates careful consideration of selectivity and potential systemic toxicities related to broad transcriptional inhibition [PubMed: 29431944]. These agents are currently being evaluated in clinical trials for their ability to overcome resistance to standard-of-care therapies in advanced cancers [PubMed: 31235518].

Other names

Histone acetyltransferase p300p300KAT3BEP300 bromodomain

Bromodomain inhibition prevents the protein from binding to acetylated lysine residues on histones and other proteins, thereby disrupting the recruitment of transcriptional machinery and inhibiting the expression of oncogenic drivers [PubMed: 27105300].