The molecular glue CLEO4-88 inhibits the ACAA1 thiolase by induced binding to GID4.

CLEO4-88 acts as a molecular glue with an EC50 of 12.5 nM to inhibit ACAA1 thiolase by inducing binding to GID4 in vitro and in cells.

• Why it matters: Understanding how small molecules can modulate protein interactions offers new avenues for regulating enzyme activity and developing targeted therapies beyond protein degradation.
• What they did: The researchers identified CLEO4-88 as a molecular glue that binds exclusively to GID4, causing a conformational change that promotes interaction with ACAA1 and inhibits its enzymatic activity through an allosteric mechanism.
• The result: This discovery demonstrates a novel approach to enzyme inhibition via induced protein-protein interactions, expanding potential strategies for enzyme regulation and therapeutic intervention.