Broad Target Screening Reveals Abundance of FKBP12-Based Molecular Glues in Focused Libraries

Abstract

Competitive (nondegradative) molecular glues represent a promising drug modality that remains underexplored primarily due to the lack of adequate hit identification approaches. In this study, we screened our historically grown FKBP-focused library containing >1000 drug-like molecules to identify FKBP-assisted molecular glues targeting a diverse panel of 57 proteins. In addition to establishing a robust and generalizable screening approach, we discovered three novel FKBP-dependent molecular glues targeting PTPRN, BRD4^BD2, and STAT4. Our results demonstrate that molecular glues are more common than previously thought and that they can be identified by repurposing existing focused libraries. An optimized, highly cooperative FKBP12-BRD4^BD2 glue demonstrated the involvement of the BD2 pocket and exhibited selectivity over the closely related BD1 domain. Our results underscore the value of FKBP12-assisted molecular glues to target challenging proteins with the potential for high selectivity.