Nuclear factor kappa-light-chain-enhancer of activated B cells p65–CREB-binding protein transcriptional coactivator complex (NF-κB p65–CBP complex)

The Nuclear factor kappa-light-chain-enhancer of activated B cells p65–CREB-binding protein (NF-κB p65–CBP) transcriptional coactivator complex is a critical molecular assembly that regulates the expression of genes involved in inflammation, immunity, and cell survival (UniProt, 2023). The complex forms when the p65 (RelA) subunit of the NF-κB transcription factor, typically after being phosphorylated at Ser276, recruits the CREB-binding protein (CBP) to the promoter or enhancer regions of target genes (NIH, 1998). CBP serves as a coactivator by providing a scaffold for the transcriptional machinery and utilizing its histone acetyltransferase (HAT) activity to modify chromatin structure, thereby facilitating gene transcription (Reactome, 2022). Dysregulation of this complex is a major driver in the pathogenesis of various cancers and chronic inflammatory diseases, where constitutive NF-κB activity promotes tumor growth, resistance to apoptosis, and the overproduction of pro-inflammatory cytokines (NIH, 2012). Consequently, the p65–CBP interaction has emerged as a high-value therapeutic target (MDPI, 2021). Current drug development strategies focus on small molecules that can selectively disrupt the protein-protein interaction between p65 and the KIX domain of CBP, as well as inhibitors of CBP's HAT and bromodomains (ACS, 2023). These approaches aim to provide more targeted therapy with reduced systemic toxicity compared to broad NF-κB pathway blockers like proteasome or IKK inhibitors (NIH, 2021).

Other names

RelA–CBP complexp65–CBP complexNF-kappaB p65–CREB-binding protein complexNF-κB p65–CBP/p300 complexp65–CBP/p300 transcriptional coactivator complex

Inhibition of the protein-protein interaction between the p65 transactivation domain and the CBP KIX domain; inhibition of the histone acetyltransferase (HAT) activity of CBP/p300; competitive binding to the CBP bromodomain.