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. Epub 2017 Sep 11.


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.

MeSH terms

  • Cell Proliferation / drug effects
  • Chromosome Segregation / drug effects
  • DNA Damage / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, myc
  • Humans
  • Mitosis / drug effects
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Protein Processing, Post-Translational
  • Small Ubiquitin-Related Modifier Proteins / antagonists & inhibitors*
  • Sumoylation*
  • Tumor Cells, Cultured


  • Enzyme Inhibitors
  • Small Ubiquitin-Related Modifier Proteins

Associated data

  • PubChem-Substance/340588393
  • PubChem-Substance/340588394
  • PubChem-Substance/340588395
  • PubChem-Substance/340588396
  • PubChem-Substance/340588397
  • PubChem-Substance/340588398