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

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 modu...

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Autores principales: Amelio, Ivano, Landré, Vivien, Knight, Richard A., Lisitsa, Andrey, Melino, Gerry, Antonov, Alexey V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496386/
https://www.ncbi.nlm.nih.gov/pubmed/25991664
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author Amelio, Ivano
Landré, Vivien
Knight, Richard A.
Lisitsa, Andrey
Melino, Gerry
Antonov, Alexey V.
author_facet Amelio, Ivano
Landré, Vivien
Knight, Richard A.
Lisitsa, Andrey
Melino, Gerry
Antonov, Alexey V.
author_sort Amelio, Ivano
collection PubMed
description 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.
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spelling pubmed-44963862015-07-15 Polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems Amelio, Ivano Landré, Vivien Knight, Richard A. Lisitsa, Andrey Melino, Gerry Antonov, Alexey V. Oncotarget 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. Impact Journals LLC 2015-04-23 /pmc/articles/PMC4496386/ /pubmed/25991664 Text en Copyright: © 2015 Amelio et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Review
Amelio, Ivano
Landré, Vivien
Knight, Richard A.
Lisitsa, Andrey
Melino, Gerry
Antonov, Alexey V.
Polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems
title Polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems
title_full Polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems
title_fullStr Polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems
title_full_unstemmed Polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems
title_short Polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems
title_sort polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496386/
https://www.ncbi.nlm.nih.gov/pubmed/25991664
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