Androgen receptor–E1A binding protein p300 protein–protein interface (AR–p300 interface)

The Androgen receptor–E1A binding protein p300 protein–protein interface is a vital regulatory interaction between the androgen receptor (AR), a ligand-dependent transcription factor, and E1A binding protein p300 (EP300), a multi-domain transcriptional coactivator and histone acetyltransferase (UniProt: P10275, Q09472). In normal physiology, this interaction facilitates the expression of genes necessary for male development and maintenance. However, in the context of prostate cancer, particularly castration-resistant prostate cancer (CRPC), the AR-p300 interface becomes a driver of disease progression by maintaining AR-mediated gene transcription even under androgen-depleted conditions (PubMed: 30212455). p300 binds to the AR through various domains, including its bromodomain and KIX domain, which recognize specific motifs on the AR. Therapeutic targeting of this interface, often via small-molecule inhibitors of the p300 bromodomain like CCS1477 (Inobrodib), aims to decouple AR from its coactivator, effectively silencing the AR signaling axis (ClinicalTrials.gov: NCT03568331). This strategy is especially promising for treating tumors expressing AR splice variants, such as AR-V7, which lack the ligand-binding domain targeted by conventional therapies but still require p300 for transcriptional activity (PubMed: 31434690). By disrupting this protein-protein interaction, drugs can inhibit the oncogenic transcriptional program without directly competing with androgens at the AR ligand-binding site.

Other names

Androgen receptor–p300 interactionAR-EP300 interfaceAndrogen receptor-p300 complexAR-CBP/p300 interface

Disruption of the physical interaction between the androgen receptor and the p300 coactivator, typically by binding to the p300 bromodomain or the AR activation function domains, thereby preventing the recruitment of the transcriptional machinery to AR-target genes.