Targeting Transcriptional Coactivators p300/CBP: Small-Molecule Inhibitors or Bifunctional Proximity-Inducing Modalities?

Abstract p300 and its paralog CBP are multifunctional transcriptional coactivators that play central roles in epigenetic regulation by integrating diverse signaling pathways. Dysregulation of p300/CBP is closely linked to cancer and other diseases, rendering them attractive therapeutic targets. Several small-molecule inhibitors of p300/CBP, including CCS1477 and FT-7051, have advanced into clinical trials for cancer treatment. In this perspective, we provide a comprehensive overview of small-molecule inhibitors targeting the bromodomain and catalytic domain of p300/CBP, with particular emphasis on their optimization processes. Furthermore, the landscape of p300/CBP-targeted drug discovery has evolved from conventional inhibitors to sophisticated bifunctional proximity-inducing modalities. We discuss the transformative impact of bifunctional molecules targeting p300/CBP, including PROTACs, AceTAGs, RIPTACs, DALTACs, and TCIPs. Finally, we discuss current limitations and challenges and offer perspectives on future directions. This perspective aims to provide a strategic roadmap for the development of next-generation therapeutics targeting p300/CBP.