Bivalent Ligands for Protein Degradation in Drug Discovery

Targeting the “undruggable” proteome remains one of the big challenges in drug discovery. Recent innovations in the field of targeted protein degradation and manipulation of the ubiquitin-proteasome system open up new therapeutic approaches for disorders that cannot be targeted with conventional inh...

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Main Authors: Marcel Scheepstra, Koen F.W. Hekking, Luc van Hijfte, Rutger H.A. Folmer
Format: Article
Language:English
Published: Elsevier 2019-01-01
Series:Computational and Structural Biotechnology Journal
Online Access:http://www.sciencedirect.com/science/article/pii/S2001037018302587
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spelling doaj-db4f8ae381d842e897739ae21a36e5992020-11-25T01:37:01ZengElsevierComputational and Structural Biotechnology Journal2001-03702019-01-0117160176Bivalent Ligands for Protein Degradation in Drug DiscoveryMarcel Scheepstra0Koen F.W. Hekking1Luc van Hijfte2Rutger H.A. Folmer3Mercachem BV, Kerkenbos 1013, 6546 BB, Nijmegen, the NetherlandsMercachem BV, Kerkenbos 1013, 6546 BB, Nijmegen, the NetherlandsMercachem BV, Kerkenbos 1013, 6546 BB, Nijmegen, the NetherlandsCorresponding author.; Mercachem BV, Kerkenbos 1013, 6546 BB, Nijmegen, the NetherlandsTargeting the “undruggable” proteome remains one of the big challenges in drug discovery. Recent innovations in the field of targeted protein degradation and manipulation of the ubiquitin-proteasome system open up new therapeutic approaches for disorders that cannot be targeted with conventional inhibitor paradigms. Proteolysis targeting chimeras (PROTACs) are bivalent ligands in which a compound that binds to the protein target of interest is connected to a second molecule that binds an E3 ligase via a linker. The E3 protein is usually either Cereblon or Von Hippel-Lindau. Several examples of selective PROTAC molecules with potent effect in cells and in vivo models have been reported. The degradation of specific proteins via these bivalent molecules is already allowing for the study of biochemical pathways and cell biology with more specificity than was possible with inhibitor compounds. In this review, we provide a comprehensive overview of recent developments in the field of small molecule mediated protein degradation, including transcription factors, kinases and nuclear receptors. We discuss the potential benefits of protein degradation over inhibition as well as the challenges that need to be overcome. Keywords: PROTAC, Protein degradation, Degrader, Proteasome, Chimera, Bivalent ligandhttp://www.sciencedirect.com/science/article/pii/S2001037018302587
collection DOAJ
language English
format Article
sources DOAJ
author Marcel Scheepstra
Koen F.W. Hekking
Luc van Hijfte
Rutger H.A. Folmer
spellingShingle Marcel Scheepstra
Koen F.W. Hekking
Luc van Hijfte
Rutger H.A. Folmer
Bivalent Ligands for Protein Degradation in Drug Discovery
Computational and Structural Biotechnology Journal
author_facet Marcel Scheepstra
Koen F.W. Hekking
Luc van Hijfte
Rutger H.A. Folmer
author_sort Marcel Scheepstra
title Bivalent Ligands for Protein Degradation in Drug Discovery
title_short Bivalent Ligands for Protein Degradation in Drug Discovery
title_full Bivalent Ligands for Protein Degradation in Drug Discovery
title_fullStr Bivalent Ligands for Protein Degradation in Drug Discovery
title_full_unstemmed Bivalent Ligands for Protein Degradation in Drug Discovery
title_sort bivalent ligands for protein degradation in drug discovery
publisher Elsevier
series Computational and Structural Biotechnology Journal
issn 2001-0370
publishDate 2019-01-01
description Targeting the “undruggable” proteome remains one of the big challenges in drug discovery. Recent innovations in the field of targeted protein degradation and manipulation of the ubiquitin-proteasome system open up new therapeutic approaches for disorders that cannot be targeted with conventional inhibitor paradigms. Proteolysis targeting chimeras (PROTACs) are bivalent ligands in which a compound that binds to the protein target of interest is connected to a second molecule that binds an E3 ligase via a linker. The E3 protein is usually either Cereblon or Von Hippel-Lindau. Several examples of selective PROTAC molecules with potent effect in cells and in vivo models have been reported. The degradation of specific proteins via these bivalent molecules is already allowing for the study of biochemical pathways and cell biology with more specificity than was possible with inhibitor compounds. In this review, we provide a comprehensive overview of recent developments in the field of small molecule mediated protein degradation, including transcription factors, kinases and nuclear receptors. We discuss the potential benefits of protein degradation over inhibition as well as the challenges that need to be overcome. Keywords: PROTAC, Protein degradation, Degrader, Proteasome, Chimera, Bivalent ligand
url http://www.sciencedirect.com/science/article/pii/S2001037018302587
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