Proteolysis Targeting Chimeras (PROTACs): A Perspective on Integral Membrane Protein Degradation

Camilla Ruffilli; Sascha Roth; Monica Rodrigo; Helen Boyd; Noam Zelcer; Kevin Moreau

doi:https://doi.org/10.1021/acsptsci.2c00142

Proteolysis Targeting Chimeras (PROTACs): A Perspective on Integral Membrane Protein Degradation

Camilla Ruffilli, Sascha Roth, Monica Rodrigo, Helen Boyd, Noam Zelcer, Kevin Moreau

Research output: Contribution to journal › Review article › Academic › peer-review

18 Citations (Scopus)

Abstract

Targeted protein degradation (TPD) is a promising therapeutic modality to modulate protein levels and its application promises to reduce the "undruggable"proteome. Among TPD strategies, Proteolysis TArgeting Chimera (PROTAC) technology has shown a tremendous potential with attractive advantages when compared to the inhibition of the same target. While PROTAC technology has had a significant impact in scientific research, its application to degrade integral membrane proteins (IMPs) is still in its beginnings. Among the 15 compounds having entered clinical trials by the end of 2021, only two targets are membrane-associated proteins. In this review we are discussing the potential reasons which may underlie this, and we are presenting new tools that have been recently developed to solve these limitations and to empower the use of PROTACs to target IMPs.

Original language	English
Pages (from-to)	849-858
Number of pages	10
Journal	ACS Pharmacology and Translational Science
Volume	5
Issue number	10
Early online date	2022
DOIs	https://doi.org/10.1021/acsptsci.2c00142
Publication status	Published - 14 Oct 2022

Keywords

AbTAC
LYTAC
PROTAC
integral membrane proteins
molecular glues
targeted degradation

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AU - Boyd, Helen

AU - Zelcer, Noam

AU - Moreau, Kevin

N1 - Funding Information: This project has received funding from the European Union’s Horizon 2020 Research and Innovation programme under the Marie Skłodowska-Curie Grant Agreement 953489 as part of the EndoConnect training expertise. Noam Zelcer is supported by a Vici grant from The Netherlands Organization for Scientific Research (NWO; 016.176.643). Publisher Copyright: © 2022 American Chemical Society.

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AB - Targeted protein degradation (TPD) is a promising therapeutic modality to modulate protein levels and its application promises to reduce the "undruggable"proteome. Among TPD strategies, Proteolysis TArgeting Chimera (PROTAC) technology has shown a tremendous potential with attractive advantages when compared to the inhibition of the same target. While PROTAC technology has had a significant impact in scientific research, its application to degrade integral membrane proteins (IMPs) is still in its beginnings. Among the 15 compounds having entered clinical trials by the end of 2021, only two targets are membrane-associated proteins. In this review we are discussing the potential reasons which may underlie this, and we are presenting new tools that have been recently developed to solve these limitations and to empower the use of PROTACs to target IMPs.

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Proteolysis Targeting Chimeras (PROTACs): A Perspective on Integral Membrane Protein Degradation

Abstract

Keywords

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