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

作者：Yaxi Yang, Rukang Zhang, Zhaojun Li, Lianghe Mei, Shili Wan, Hong Ding, Zhifeng Chen, Jing Xing, Huijin Feng, Jie Han, Hualiang Jiang, Mingyue Zheng, Cheng Luo, Bing Zhou · 发表于：Journal of Medicinal Chemistry · 年份：2020 · DOI：10.1021/acs.jmedchem.9b01721 · 被引用次数：132 · 研究领域：Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways、Genomics and Chromatin Dynamics

p300 and CREB-binding protein (CBP) are ubiquitously expressed pleiotropic lysine acetyltransferases 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, druglike 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 druglike properties, exemplified by B026 . Our data demonstrated that B026, with half maximal inhibitory concentration (IC 50 ) values 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.