Ubiquitin-activating enzyme (E1), which catalyzes the activation of ubiquitin in the initial step of the ubiquitination cascade, is a potential therapeutic target in multiple myeloma and breast cancer treatment. However, only a few E1 inhibitors have been reported to date. Moreover, there has been little medicinal chemistry research on the three-dimensional structure of E1. Therefore, in the present study, we attempted to identify novel E1 inhibitors using structure-based drug design. Following the rational design, synthesis, and in vitro biological evaluation of several such compounds, we identified a reversible E1 inhibitor (4b). Compound 4b increased p53 levels in MCF-7 breast cancer cells and inhibited their growth. These findings suggest that reversible E1 inhibitors are potential anticancer agents.

泛素激活酶（E1）在泛素化级联反应的初始阶段催化泛素的激活，是多发性骨髓瘤和乳腺癌治疗的潜在治疗靶标。但是，迄今为止，仅报道了几种E1抑制剂。而且，关于E1的三维结构的药物化学研究很少。因此，在本研究中，我们尝试使用基于结构的药物设计来鉴定新型E1抑制剂。经过合理设计，合成和几种此类化合物的体外生物学评估，我们确定了可逆的E1抑制剂（4b）。化合物4b增加MCF-7乳腺癌细胞中的p53水平并抑制其生长。这些发现表明可逆的E1抑制剂是潜在的抗癌药。