Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer

J Med Chem. 2021 Mar 11;64(5):2501-2520. doi: 10.1021/acs.jmedchem.0c01491. Epub 2021 Feb 25.


SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Adenosine / therapeutic use
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Mice
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Protein Binding
  • Protein Processing, Post-Translational / drug effects
  • Structure-Activity Relationship
  • Sulfonic Acids / chemical synthesis
  • Sulfonic Acids / metabolism
  • Sulfonic Acids / therapeutic use*
  • Sumoylation / drug effects*
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors*
  • Ubiquitin-Activating Enzymes / metabolism
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Sulfonic Acids
  • Ubiquitin-Activating Enzymes
  • Adenosine