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An Optimized RNF126-Targeting Covalent Handle for Molecular Glue Degraders
Aman Modi1,2,3, Ethan S Toriki1,2,3,4, Christian E Stieger1,2,3
1Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, California USA 94720.
Biorxiv : the Preprint Server for Biology
|March 23, 2026
Summary
Researchers developed an improved molecular glue degrader using a stabilized RNF126-targeting handle. This new tool effectively degrades target proteins like BRD4 and androgen receptor variants in cancer cells, advancing targeted protein degradation therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Molecular glue degraders offer a novel approach to target proteins resistant to traditional inhibition.
- Rational design principles for molecular glues are not well-established.
- Previous work identified a fumarate-based handle targeting RNF126, but its reactivity and cytotoxicity limited clinical use.
Purpose of the Study:
- To develop an optimized, metabolically stabilized covalent handle targeting RNF126 for molecular glue degraders.
- To create potent and selective degraders for therapeutic targets, including previously undruggable variants.
Main Methods:
- Design and synthesis of a novel covalent handle with a trans-cyclobutane linker.
- Appended the handle to known ligands (JQ1, AR/AR-V7 targeting) to create new degraders.
- Evaluated degradative activity, selectivity, and cytotoxicity in cancer cell models.
Main Results:
- The optimized handle showed reduced glutathione reactivity and cytotoxicity while maintaining degradative efficacy.
- A JQ1-conjugated degrader selectively eliminated BRD4 in an RNF126-dependent manner.
- The handle enabled degradation of androgen receptor (AR) and AR-V7 in prostate cancer cells, surpassing enzalutamide's efficacy.
Conclusions:
- An optimized RNF126-targeting covalent handle facilitates the rational design of molecular glue degraders.
- This approach is effective against transcriptional regulators, including challenging targets like AR-V7.
- The developed degraders show promise for treating cancers driven by AR signaling.
