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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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 |
work_keys_str_mv |
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