Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor PMID: 28892090

ADC Targets in Oncology

2026-04-10

Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor

Nat Chem Biol. 2017 Nov;13(11):1164-1171. doi: 10.1038/nchembio.2463.

Xingyue He ¹ , Jessica Riceberg ¹ , Teresa Soucy ¹ , Erik Koenig ¹ , James Minissale ¹ , Melissa Gallery ¹ , Hugues Bernard ¹ , Xiaofeng Yang ¹ , Hua Liao ¹ , Claudia Rabino ¹ , Pooja Shah ¹ , Kristina Xega ¹ , Zhong-Hua Yan ¹ , Mike Sintchak ¹ , John Bradley ¹ , He Xu ¹ , Matt Duffey ¹ , Dylan England ¹ , Hirotake Mizutani ¹ , Zhigen Hu ¹ , Jianping Guo ¹ , Ryan Chau ¹ , Lawrence R Dick ¹ , James E Brownell ¹ , John Newcomb ¹ , Steve Langston ¹ , Eric S Lightcap ¹ , Neil Bence ¹ , Sai M Pulukuri ¹

Affiliations

Abstract

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.