Related Experiment Video
Updated: May 10, 2025
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Targeted protein degradation in oncology: novel therapeutic opportunity for solid tumours?
Noé Herbel1,2,3, Sophie Postel-Vinay1,2,4
1ERC Chromatin Remodelling, DNA Repair and Epigenetics Laboratory, INSERM Unit U981, Gustave Roussy Institute, Villejuif, France.
Abstract:
Targeted and immune therapies have improved patient outcomes in selected diseases. Still, resistance inevitably occurs, and a significant portion of the proteome remains undruggable due to target localisation, structural or functional constraints. Targeted protein degraders (TPDs) represent a promising strategy to expand druggable targets by redirecting the ubiquitin-proteasome system to selectively degrade proteins of interest (POI). TPDs include proteolysis-targeting chimeras (PROTACs), which are heterobifunctional molecules that create a ternary complex with the POI and the E3 ligase, and molecular glues (MGs), which are monovalent small molecules that create an interface between an E3 ligase and the POI. Here, we provide a viewpoint on novel therapeutic opportunities offered by TPDs, notably through the targeting of previously undruggable proteins or overcoming some resistance mechanisms. We further present challenges that will need to be addressed in order to optimise clinical development, including dose optimisation, patient selection and drug delivery.
Insights
Targeted protein degraders (TPDs) offer new ways to treat diseases by degrading disease-causing proteins. This approach expands treatment options for previously undruggable targets and resistance mechanisms.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Targeted and immune therapies have limitations, including inevitable resistance and undruggable targets.
- A significant portion of the proteome remains inaccessible to conventional therapeutics due to various constraints.
Purpose of the Study:
- To provide a viewpoint on novel therapeutic opportunities presented by Targeted Protein Degraders (TPDs).
- To highlight the potential of TPDs in targeting previously undruggable proteins and overcoming resistance mechanisms.
Main Methods:
- Discussion of TPDs, including proteolysis-targeting chimeras (PROTACs) and molecular glues (MGs).
- Exploration of the mechanism of action involving the ubiquitin-proteasome system and ternary complex formation.
Main Results:
- TPDs represent a promising strategy to expand the druggable proteome.
- TPDs can selectively degrade proteins of interest (POIs) by hijacking cellular degradation machinery.
Conclusions:
- TPDs offer novel therapeutic avenues for diseases with limited treatment options.
- Challenges in clinical development, such as dose optimization, patient selection, and drug delivery, require further investigation.
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