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Charged molecular glue discovery enabled by targeted degron display.

Zhe Zhuang¹, Woong Sub Byun^1,2, Jakub Chrustowicz³

¹Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.

Nature Chemical Biology

|April 6, 2026

Summary

This summary is machine-generated.

Researchers discovered ZZ1, a novel molecular glue degrader (MGD) that targets BET-family proteins. This prodrug activates to form a charged glue, enabling targeted protein destruction and advancing drug discovery for challenging targets.

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Area of Science:

Medicinal Chemistry
Molecular Biology
Drug Discovery

Background:

Small molecules inducing protein interactions are vital for medicine and research.
Targeted protein degradation has accelerated interest in molecular glue degraders (MGDs).
MGDs reshape protein surfaces to promote ubiquitylation and target protein destruction.

Purpose of the Study:

To address the challenge of discovering MGDs for specific targets.
To introduce a 'chemocentric' approach for MGD discovery.
To identify novel MGDs for BET-family proteins and explore new degron binding mechanisms.

Main Methods:

Chemocentric discovery of ZZ1, a BET-family protein degrader.
ZZ1 was identified as a prodrug that unmasks a sulfinic acid upon activation.
Investigation of ZZ1's binding to the CTLH ubiquitin ligase complex via the YPEL5 subunit.

Main Results:

ZZ1 acts as a prodrug, releasing an active, negatively charged glue.
The activated glue binds to a basic pocket in the YPEL5 subunit of the CTLH ligase complex.
This interaction demonstrates YPEL5's role in recruiting CTLH substrates.

Conclusions:

Successful chemocentric discovery of ZZ1, a novel BET-family MGD.
Unveiled a new mechanism for MGDs utilizing acidic and basic degrons.
Established YPEL5's capacity to recruit CTLH substrates, opening avenues for new MGD development.