HECT E3 泛素连接酶 1 (WWP1) 和 2 (WWP2) 负责泛素介导的关键肿瘤抑制蛋白的降解，并且在各种癌症和疾病中失调。在这里，我们通过鉴定 NSC-217913 来扩展其有限的抑制剂空间，该 NSC-217913 的 WWP1 IC50 为 158.3μM（95% CI = 128.7, 195.1μM）。分子对接辅助合成方法的结构-活性关系导致化合物 11 显示出增强的效力，WWP1 的 IC50 为 32.7μM (95% CI = 24.6, 44.3μM)，IC50 为 269.2μM (95% CI = 209.4, 347.9μM) ）对于WWP2。分子对接产生的活性位点结合姿势表明杂环咪唑并[4,5-b]吡嗪支架与酪氨酸的酚基团发生π堆积相互作用，而乙酯能够实现强的离子偶极相互作用。鉴于WWP1和WWP2的治疗潜力，我们建议化合物11可以为未来先导化合物的开发提供基础。

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.