Cyclic AMP-response element binding protein (CREB), a downstream transcription factor of multiple signaling pathways, is overexpressed in many different types of cancers. Thus, targeting CREB has great potential for the development of antitumor agents. Peptidic foldamers have emerged as a powerful tool to disrupt disease-related protein–protein interactions (PPIs) with chemodiversity and high stability towards enzymatic degradation. Herein, we harnessed several hydrophobic groups of helical sulfonyl-γ-AApeptide foldamer targeting the hydrophobic grooves on the surface of the KIX domain of CREB binding protein (CBP), to disrupt CREB/CBP PPI. We showed that several stapled sulfonyl-γ-AApeptides could suppress CREB-mediated gene transcription and exhibit effective antiproliferative activity in cell-based assays and demonstrate its potency in inhibiting tumor growth in vivo. Our studies suggest that sulfonyl-γ-AApeptides as a class of helical foldamer could mimic the helical kinase-inducible activation domain of CREB (KID) to target the hydrophobic grooves on the surface of CBP KIX domain, and thereby inhibiting KIX–KID interaction, which provides a new strategy for the development of antitumor agent by targeting PPIs involving intrinsically disordered proteins (IDPs).

CREB/CBP interaction  /  KIX domain  /  IDPs  /  PPI inhibitors  /  Helical foldamers  /  Peptidomimetics  /  Sulfonyl-γ-AApeptides  /  Stapled peptides