Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, thus decreasing cancer cell proliferation. Moreover, we found that induction of the MYC oncogene increased the ML-792-mediated viability effect in cancer cells, thus indicating a potential application of SAE inhibitors in treating MYC-amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic-subunit (UBA2) S95N M97T mutant rescued SUMOylation loss and the mitotic defect induced by ML-792, thus confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins, thereby facilitating novel insights into SUMO biology.

小泛素样修饰子（SUMO）家族蛋白通过翻译后修饰来调节靶标蛋白的功能。然而，一直缺乏靶向SUMO途径的有效和选择性抑制剂。在这里，我们描述ML-792，这是一种基于机制的SUMO活化酶（SAE）抑制剂，在细胞测定中具有纳摩尔浓度。ML-792有选择地阻断SAE酶的活性和总SUMOylation，从而减少癌细胞的增殖。此外，我们发现MYC致癌基因的诱导增加了癌细胞中ML-792介导的生存力作用，从而表明SAE抑制剂在治疗MYC中有潜在的用途。-放大的肿瘤。使用ML-792，我们进一步探索了SUMOylation在有丝分裂进程和染色体分离中的关键作用。此外，SAE催化亚基（UBA2）S95N M97T突变体的表达挽救了SUMOylation损失和ML-792诱导的有丝分裂缺陷，从而证实了ML-792的选择性。作为一种有效且选择性的SAE抑制剂，ML-792可快速损失内源性SUMO酰化的蛋白质，从而促进对SUMO生物学的新见解。