Medicinal chemistry approaches to the discovery and development of p300/CBP inhibitors for cancer therapy

Abstract

p300 and CBP (CREB-binding protein) are homologous histone acetyltransferases (HATs) that function as transcriptional co-activators, playing pivotal roles in regulating gene expression through acetylation of histones and transcription factors. Their dysregulation has been implicated in various cancers, making them attractive targets for therapeutic intervention. Significant advancements have been made in the discovery and development of small-molecule inhibitors targeting p300/CBP. These efforts have led to the identification of potent and selective inhibitors, such as A-485, which specifically targets the HAT domain, demonstrating notable antitumor activity in preclinical models. Structure-based drug design and high-throughput screening have facilitated the optimization of these inhibitors, enhancing their selectivity and pharmacokinetic properties. Additionally, the development of covalent inhibitors and PROTACs (proteolysis-targeting chimeras) has expanded the arsenal against p300/CBP, offering novel mechanisms to modulate their activity. With several inhibitors progressing into clinical trials, the therapeutic potential of targeting p300/CBP in oncology is becoming increasingly evident. This review examines p300/CBP inhibitors reported from 2019, focusing on the medicinal chemistry optimization strategies.