Related Experiment Video
Updated: Aug 6, 2026
Spatiotemporally Controlled Nuclear Translocation of Guests in Living Cells Using Caged Molecular Glues as Photoactivatable Tags
Published on: January 17, 2019
An optimized RNF126-targeting covalent handle for molecular glue degraders
Aman Modi1, Ethan S Toriki2, Christian E Stieger1
1Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Novartis-Berkeley Translational Chemical Biology Institute, USA.
Researchers developed a new molecular glue degrader strategy using an optimized covalent handle. This approach effectively targets and degrades proteins like BRD4 and androgen receptor variants in prostate cancer cells, offering a promising therapeutic avenue.
Area of Science:
- Chemical Biology
- Drug Discovery
- Molecular Oncology
Background:
- Molecular glue degraders offer a novel therapeutic strategy for previously undruggable proteins.
- Rational design principles for molecular glues are not well-established, hindering their development.
- Previous work identified a fumarate-based handle for RNF126-mediated protein degradation, but its reactivity and toxicity limited clinical use.
Purpose of the Study:
- To develop an optimized, metabolically stabilized covalent handle for RNF126-targeting molecular glue degraders.
- To assess the efficacy of the new handle in degrading target proteins, including BRD4 and androgen receptor variants.
- To evaluate the therapeutic potential of RNF126-based degraders in prostate cancer models.
Main Methods:
- Design and synthesis of a novel trans-cyclobutane linker-based covalent handle for RNF126.
- Appended the optimized handle to known ligands (JQ1 and an androgen receptor ligand) to create new degraders.
- Assessed degradative activity, selectivity, cytotoxicity, and mechanism of action in relevant cellular models, including prostate cancer cells.
Main Results:
- The optimized handle demonstrated reduced glutathione reactivity and cytotoxicity compared to the fumarate handle while retaining potent degradative activity.
- The new handle successfully generated a potent and selective BRD4 degrader when conjugated to JQ1, dependent on RNF126.
- Transplantation of the handle onto a non-inhibitory androgen receptor ligand enabled potent degradation of both AR and AR-V7 in prostate cancer cells, surpassing enzalutamide's efficacy.
Conclusions:
- An optimized RNF126-targeting covalent handle provides a viable strategy for developing potent molecular glue degraders.
- This approach enables the rational design of degraders against challenging targets, including transcription factors like BRD4 and AR.
- The developed molecular glues show promise for targeting undruggable variants like AR-V7 in androgen-independent prostate cancer.
More Related Videos
05:33High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
06:10A Fluorescence-based Exonuclease Assay to Characterize DmWRNexo, Orthologue of Human Progeroid WRN Exonuclease, and Its Application to Other Nucleases
Published on: December 23, 2013