Charged molecular glue discovery enabled by targeted degron display

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.