Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors.
Yaxi YangRukang ZhangZhaojun LiLianghe MeiShili WanHong DingZhifeng ChenJing XingHuijin FengJie HanHualiang JiangMingyue ZhengCheng LuoBing ZhouPublished in: Journal of medicinal chemistry (2020)
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 (IC50) 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.
Keyphrases
- small molecule
- artificial intelligence
- drug discovery
- big data
- binding protein
- machine learning
- dna methylation
- anti inflammatory
- photodynamic therapy
- endothelial cells
- gene expression
- oxidative stress
- transcription factor
- high throughput
- squamous cell carcinoma
- body composition
- resistance training
- induced pluripotent stem cells
- lymph node metastasis
- amino acid
- mesenchymal stem cells