Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors.

p300/CBP are ubiquitously expressed pleiotropic lysine acetyl transferases and play a key role as transcriptional co-activators that are essential for a multitude of cellular processes. Despite great importance, there is a lack of highly selective, potent, drug-like p300/CBP inhibitors. Through the artificial intelligence-assisted drug discovery pipeline and further optimization, we reported the discovery of novel, highly selective, potent small molecule inhibitors of p300/CBP histone acetyltransferases (HAT) with desired drug-like properties, exemplified by B026. Our data demonstrated that B026, with an IC50 value of 1.8 nM to p300 and 9.5 nM to CBP enzyme inhibitory activity, is the most potent, selective p300/CBP HAT inhibitor. Moreover, B026 achieves significant and dose-dependent tumor growth inhibition in an animal model of human cancer, suggesting that B026 is a highly promising p300/CBP HAT inhibitor and warrants extensive preclinical investigation as a potential clinical development candidate.