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
  • 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.

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