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

Chetan K. Chana

doi:10.1038/s41589-026-02183-4

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

2026-04-09

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DOI：10.1038/s41589-026-02183-4

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Molecular glues promote protein–protein interactions by enhancing the surface complementarity between proteins. Those that recruit an E3 ubiquitin ligase to a target can elicit ubiquitination and subsequent destruction of the target protein—a mechanism that underpins the field of targeted protein degradation (TPD). Here we explored whether small-molecule binders to the CTLH E3 ligase subunit GID4 could act as molecular glues. We discovered that CLEO4-88 functions as a molecular glue (EC50 = 12.5 nM) to promote the interaction of GID4 with the peroxisomal thiolase ACAA1 in vitro and in cellulo. An atomic structure of the ternary complex revealed an allosteric mechanism whereby CLEO4-88 binds solely to GID4 and induces a conformational change conducive to binding ACAA1. Biochemical analysis demonstrated that, while ACAA1 cannot be recruited by GID4 to a CTLH holoenzyme for ubiquitination, ternary complex formation inhibits ACAA1 thiolase activity, thus demonstrating potential utility beyond TPD. A small molecule, CLEO4-88, was identified that acts as a molecular glue, linking the E3 ligase subunit GID4 with ACAA1. Instead of triggering ACAA1 degradation, the compound inhibits its enzymatic activity.

Keywords:

Enzyme mechanisms

Mechanism of action

Small molecules

Target identification

X-ray crystallography

Chemistry/Food Science

general

Biochemical Engineering

Biochemistry

Cell Biology

Bioorganic Chemistry

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

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