Histone acetyltransferases (HATs) play a crucial role in post-translational modification. Among them, overexpression, mutation, or hyperfunction of EP300/CBP has been associated with various cancers. In this study, we identified the novel compound 2-chloro-5-[5-[(E)-[1-(3-chlorophenyl)-3-methyl-5-oxo-pyrazol-4-ylidene]methyl]-2-furyl]benzoic acid (1) as an EP300 HAT inhibitor via virtual screening. Further research has been focused on the design, synthesis, and in vitro biological evaluation of virtual hit derivatives. The studies revealed that 4-pyridone-3-carboxylic acid derivatives exhibited bioisosterism of benzoic acid. Replacement proved effective, providing compounds with similar EP300 HAT-inhibitory activity and improved cell growth-inhibitory activity compared to the benzoic acid analogs. Through these studies, we identified a potent and selective EP300/CBP HAT inhibitor.

组蛋白乙酰转移酶 (HAT) 在翻译后修饰中起着至关重要的作用。其中，EP300/CBP的过表达、突变或功能亢进与多种癌症有关。在这项研究中，我们鉴定了新化合物 2-chloro-5- [5 - [( E ) - [1- (3-chlorophenyl) -3-methyl-5-oxo-pyrazol-4-ylidene]methyl] -2 -furyl] benzoic acid ( 1 )通过虚拟筛选作为 EP300 HAT 抑制剂。进一步的研究集中在设计、合成和体外虚拟命中衍生物的生物学评价。研究表明，4-吡啶酮-3-羧酸衍生物表现出苯甲酸的生物等排性。替换证明是有效的，与苯甲酸类似物相比，它提供了具有相似 EP300 HAT 抑制活性和改善细胞生长抑制活性的化合物。通过这些研究，我们确定了一种有效的选择性 EP300 / CBP HAT 抑制剂。