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

Affiliation

1 Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, USA.

PMID: 28892090 DOI: 10.1038/nchembio.2463

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-108702

ML-792

99.90%, SUMO-Activating Enzyme Inhibitor

E1/E2/E3 Enzyme

Cancer

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