Polypharmacology of small molecules targeting the ubiquitin-proteasome and ubiquitin-like systems

Ivano Amelio, Vivien Landré, Richard A. Knight, Andrey Lisitsa, Gerry Melino, Alexey V. Antonov

Research output: Contribution to journalArticlepeer-review


Targeting the ubiquitin-proteasome system (UPS) and ubiquitin-like signalling systems (UBL) has been considered a promising therapeutic strategy to treat cancer, neurodegenerative and immunological disorders. There have been multiple efforts recently to identify novel compounds that efficiently modulate the activities of different disease-specific components of the UPS-UBL. However, it is evident that polypharmacology (the ability to affect multiple independent protein targets) is a basic property of small molecules and even highly potent molecules would have a number of "off target" effects. Here we have explored publicly available high-throughput screening data covering a wide spectrum of currently accepted drug targets in order to understand polypharmacology of small molecules targeting different components of the UPS-UBL. We have demonstrated that molecules targeting a given UPS-UBL protein also have high odds to target a given off target spectrum. Moreover, the off target spectrum differs significantly between different components of UPS-UBL. This information can be utilized further in drug discovery efforts, to improve drug efficiency and to reduce the risk of potential side effects of the prospective drugs designed to target specific UPS-UBL components.

Original languageEnglish
Pages (from-to)9646-9656
Number of pages11
Issue number12
Publication statusPublished - 2015


  • SUMO
  • UBC13
  • UBL
  • UCH37
  • UPS

ASJC Scopus subject areas

  • Oncology


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