Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors
Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors
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发现高效、选择性且口服有效的 p300/CBP 组蛋白乙酰转移酶抑制剂
DOI：
10.1021/acs.jmedchem.9b01721
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发表时间：
2020-02-13
影响因子：
7.3
通讯作者：
Zhou, Bing
中科院分区：
文献类型：
--
作者：
Yang, Yaxi;Zhang, Rukang;Zhou, Bing
p300和CREB结合蛋白（CBP）是广泛表达的多效性赖氨酸乙酰转移酶，并且作为转录共激活因子在许多细胞过程中起关键作用。尽管非常重要，但缺乏高选择性、有效的药物样p300/CBP抑制剂。通过人工智能辅助的药物发现管道和进一步优化，我们报告了具有所需药物样性质的新型，高选择性，有效的p300/CBP组蛋白乙酰转移酶（HAT）小分子抑制剂的发现，以B 026为例。我们的数据表明，B 026对p300和CBP酶抑制活性的半最大抑制浓度（IC 50）值分别为1.8 nM和9.5 nM，是最有效的选择性p300/CBP HAT抑制剂。此外，B 026在人类癌症动物模型中实现了显著的剂量依赖性肿瘤生长抑制，表明B 026是一种非常有前途的p300/CBP HAT抑制剂，值得作为潜在的临床开发候选物进行广泛的临床前研究。
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.