title: Polypharmacology of small molecules targeting the ubiquitin-proteasome and ubiquitin-like systems.
abstract: 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.
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: Ivano
authors.initials: I
authors.lastname: Amelio
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: Vivien
authors.initials: V
authors.lastname: Landré
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.affiliation: Institute of Biomedical Chemistry of The Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Lisitsa
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.|Department of Experimental Medicine & Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Antonov
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000737:chemistry; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D064798:Polypharmacology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D025941:Protein Interaction Mapping; D025842:SUMO-1 Protein / Q000737:chemistry; D015398:Signal Transduction; D025801:Ubiquitin / Q000737:chemistry*; D043222:Ubiquitin Thiolesterase / Q000737:chemistry; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry; D054875:Ubiquitination
chemical_list: D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D025801:Ubiquitin; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases; C408873:SENP6 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: SUMO; UBC13; UBL; UCH37; UPS