Identification of Clofibric Acid as a Synoviolin (SYVN1) Ligand for Proteolysis-Targeting Chimera (PROTAC) Development

Targeted protein degradation (TPD) via proteolysis-targeting chimeras (PROTACs) is a powerful therapeutic strategy, yet only a small fraction of the >600 human E3 ligases have been harnessed. To expand this repertoire, we developed clickable photoaffinity probes based on clinically used drugs and metabolites to identify potential E3 ligases as targets. Here, we report the discovery of clofibric acid with a molecular weight of only 214 Da as a ligand for synoviolin (SYVN1). We demonstrate its utility by developing clofibric acid–based BRD4 PROTACs. The linker length and architecture play a critical role in the target degradation efficiency. The clofibric acid-derived BRD4 PROTACs achieve selective BRD4 degradation in an SYVN1-dependent manner. Our findings establish clofibric acid as a robust addition to the TPD toolbox, offering a novel E3 ligase recruitment strategy for the development of next-generation degraders.