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 activity by inducing binding to GID4 in vitro and in cellulo.

• Why it matters: Understanding how small molecules can modulate protein interactions expands potential therapeutic strategies beyond targeted protein degradation. This work addresses the gap in knowledge about molecular glues that influence enzyme activity through induced protein binding.
• What they did: The researchers identified CLEO4-88 as a molecular glue that promotes GID4-ACAA1 interaction, determined its atomic structure revealing an allosteric binding mechanism, and showed that this interaction inhibits ACAA1 thiolase activity.
• The result: This finding suggests that molecular glues like CLEO4-88 can be used to regulate enzyme function, providing a new approach for modulating protein activity beyond degradation pathways.