Targeted Inhibition of CBP/p300–NCOA3 Interactions with an α-Methylated Peptide

The CREB-binding protein (CBP) and its paralogue p300 are cellular integrators of various signaling pathways involved in various physiological functions. Together with NCOA proteins, they act as coactivators of nuclear receptors. CBP/p300 and NCOA3 are overexpressed in endocrine cancers, leading to enhanced nuclear receptor activity and promoting tumor progression through activation of oncogenes and regulation of cellular functions. Thus, targeting CBP/p300-NCOA3 has great potential for the development of antitumor agents. As a tool to disrupt disease-related protein-protein interactions, we developed the NCOA3 activation domain 1 (AD1) peptide containing noncanonical α-methylated amino acids for targeting the intrinsically disordered nuclear coactivator binding domain (NCBD) in CBP/p300. We showed that this peptide variant binds with a stronger affinity to its target proteins than the wild-type peptide and inhibits CBP/p300 acetylase activity. This peptide variant also modulates interactomes and CBP/p300-mediated gene transcription and exhibits effective antiproliferative activity in cell-based assays.