A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment

Nat Med. 2018 Feb;24(2):186-193. doi: 10.1038/nm.4474. Epub 2018 Jan 15.

Abstract

The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA Damage / drug effects
  • DNA Repair / drug effects
  • Humans
  • Imides / pharmacology
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Nucleosides / pharmacology*
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / genetics
  • Protein Binding
  • Small Molecule Libraries / pharmacology*
  • Sulfonamides / pharmacology*
  • Ubiquitin / antagonists & inhibitors
  • Ubiquitin / chemistry
  • Ubiquitin / genetics
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors*
  • Ubiquitin-Activating Enzymes / chemistry
  • Ubiquitin-Activating Enzymes / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Imides
  • MLN7243
  • Nucleosides
  • Small Molecule Libraries
  • Sulfonamides
  • Ubiquitin
  • Proteasome Endopeptidase Complex
  • Ubiquitin-Activating Enzymes