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Published on: November 9, 2020
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Targeted protein degradation via intramolecular bivalent glues
Oliver Hsia1, Matthias Hinterndorfer2, Angus D Cowan1
1Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.
Nature
|February 21, 2024
Summary
Intramolecular bivalent glues (IBGs) represent a novel targeted protein degradation strategy. These compounds induce degradation by engaging target protein domains in cis, enhancing E3 ligase binding and promoting ubiquitination.
Area of Science:
- Pharmacology
- Molecular Biology
- Biochemistry
Background:
- Targeted protein degradation utilizes E3 ubiquitin ligases to direct proteins for proteasomal degradation.
- Existing modalities include proteolysis-targeting chimeras (PROTACs) and molecular glues.
- The mechanism of bifunctional degraders for BRD2 and BRD4 remained incompletely understood.
Purpose of the Study:
- To investigate the mechanism of action of intramolecular bivalent glues (IBGs) targeting BRD2 and BRD4.
- To elucidate how IBGs induce targeted protein degradation.
- To design improved IBG-based degraders.
Main Methods:
- Orthogonal genetic screening
- Biophysical characterization
- Structural reconstitution
- Rational drug design
Main Results:
- IBGs simultaneously engage and connect two adjacent domains of the target protein (BRD4) in cis, unlike PROTACs which connect target and ligase in trans.
- This cis engagement enhances the binding of BRD4 to E3 ligases DCAF11 or DCAF16.
- Structural data guided the development of highly potent degraders with low picomolar potency.
Conclusions:
- Intramolecular bivalent glues (IBGs) represent a new modality for targeted protein degradation.
- IBGs function by bridging protein domains in cis to improve E3 ligase interaction and ubiquitination.
- This mechanism offers a novel approach for developing potent protein degraders.
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