Inhibition of CREB binding and function with a dual-targeting ligand

Abstract

CBP/p300 is a master transcriptional coactivator, regulating gene activation by interacting with multiple transcriptional activators. Dysregulation of protein-protein interactions (PPIs) between the CBP/p300 KIX domain and its activators is implicated in a number of cancers including breast, leukemia, and colorectal cancer. However, KIX is typically considered undruggable because of its shallow binding surfaces lacking both significant topology and promiscuous binding profiles. We previously reported a dual-targeting peptide (MybLL-tide) that inhibits the KIX-Myb interaction with excellent specificity and potency. Here we demonstrate a branched, second-generation analog, CREBLL-tide, that inhibits the KIX-CREB PPI with higher potency and selectivity. Additionally, the best of these CREBLL-tide analogs shows excellent and selective anti-proliferation activity in breast cancer cells. These results indicate CREBLL-tide is an effective tool for assessing the role of KIX-activator interactions in breast cancer and expanding the dual-targeting strategy for inhibiting KIX and other coactivators that contain multiple binding surfaces.