Histone acetyltransferase p300 and CREB-binding protein bromodomains (p300/CBP BRD)

The Histone acetyltransferase p300 (EP300) and CREB-binding protein (CBP or CREBBP) are highly homologous transcriptional co-activators that play a central role in regulating gene expression through chromatin remodeling (UniProt P45973, Q92793). These proteins contain a conserved bromodomain (BRD) that functions as an epigenetic reader, specifically recognizing acetylated lysine residues on histone tails and various non-histone transcription factors (Nature Reviews Drug Discovery, 2012, 11:384-400). By binding to these acetylated marks, the p300/CBP bromodomains facilitate the recruitment of the transcriptional machinery to specific genomic loci, thereby driving the expression of genes involved in cell proliferation and survival (Cancer Discovery, 2018, 8:1-16). In many cancers, including castration-resistant prostate cancer and acute myeloid leukemia, the p300/CBP bromodomains are essential for the activity of key oncogenic drivers such as the Androgen Receptor and MYC (Molecular Cancer Therapeutics, 2021, 20:1462-1471). Therapeutic targeting of these bromodomains with small molecule inhibitors like CCS1477 (Inobrodib) aims to disrupt these oncogenic transcriptional programs, offering a promising strategy for treating tumors that have become resistant to conventional therapies (Clinical Cancer Research, 2020, 26:5876-5888). Clinical trials are currently evaluating the safety and efficacy of these inhibitors in patients with advanced solid tumors and hematological malignancies (CellCentric, 2023).

Other names

EP300 bromodomainCREBBP bromodomainKAT3A bromodomainKAT3B bromodomainp300/CBP-BDKAT3A/KAT3B bromodomains

Competitive inhibition of the bromodomain acetyl-lysine binding pocket, preventing the recruitment of p300/CBP to chromatin and inhibiting the transcription of oncogenic drivers (Nature Reviews Drug Discovery, 2012).