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.

中文翻译：

---

发现高效，选择性和口服有效的p300 / CBP组蛋白乙酰转移酶抑制剂。

p300和CREB结合蛋白（CBP）被普遍表达的多效赖氨酸乙酰基转移酶，并作为转录共激活子发挥着关键作用，而转录共激活子是许多细胞过程必不可少的。尽管非常重要，但仍缺乏高度选择性的，有效的，类似药物的p300 / CBP抑制剂。通过人工智能辅助药物发现渠道和进一步优化，我们报告了发现具有所需药物样性质的新型，高选择性，有效的p300 / CBP组蛋白乙酰基转移酶（HAT）小分子抑制剂的发现，以B026为例。我们的数据表明，B026的半数最大抑制浓度（IC50）值对p300的抑制活性为1.8 nM，对CBP酶的抑制活性为9.5 nM，是最有效的选择性p300 / CBP HAT抑制剂。此外，