Probing the Roles of SUMOylation in Cancer Cell Biology Using a Selective SAE inhibitor

Small ubiquitin-like modifier (SUMO) family proteins regulate target protein functions by post-translational modification. However, a potent and selective inhibitor to target the SUMO pathway has been lacking. Here we describe ML-792, the first mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, which leads to reduced cancer cell proliferation. Moreover, induction of the MYC oncogene increased the ML-792 mediated viability effect in cancer cells, indicating potential application of SAE inhibitors in 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) mutant S95N/M97T rescued SUMOylation loss and the mitotic defect induced by ML-792, confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins allowing for novel insights into SUMO biology. Overall design: RNA-SEQ was used to analyze changes in mRNA profiles of human colon and breast cancer cells treated with ML00754792 SAEi

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He X, Riceberg J, Soucy T, Koenig E, Minissale J, Gallery M, Bernard H, Yang X, Liao H, Rabino C, Shah P, Xega K, Yan ZH, Sintchak M, Bradley J, Xu H, Duffey M, England D, Mizutani H, Hu Z, Guo J, Chau R, Dick LR, Brownell JE, Newcomb J, Langston S, Lightcap ES, Bence N, Pulukuri SM