FKBP12-targeting PROTACs

FKBP12-targeting PROTACs (PROteolysis TArgeting Chimeras) are heterobifunctional small molecules designed to selectively degrade the FK506-binding protein 12 (FKBP12). FKBP12 is a cytosolic immunophilin that acts as a physiological regulator of various signaling pathways, including the bone morphogenetic protein (BMP) type I receptor ALK2. In multiple myeloma, targeting FKBP12 with traditional inhibitors like FK506 (tacrolimus) enhances BMP-induced SMAD1/5/8 phosphorylation and subsequent apoptosis, but is limited by calcineurin-mediated immunosuppression. FKBP12-targeting PROTACs, such as RC32 or novel bicyclic sulfonamide-based degraders, achieve highly specific degradation of FKBP12 via the ubiquitin-proteasome system (recruiting E3 ligases like Cereblon, DCAF16, or VHL) without inducing immunosuppressive effects, offering a potential therapeutic strategy for multiple myeloma and other cancers.

Other names

FKBP12 PROTACsFKBP-12 PROTACsFKBP 12 PROTACsFKBP12-targeting proteolysis-targeting chimerasFKBP-12-targeting proteolysis-targeting chimerasFKBP 12-targeting proteolysis-targeting chimeras