Development of Novel Small-Molecule Degraders of FK506-Binding Protein 51

The FK506-binding protein 51 (FKBP51) plays an important role in steroid hormone receptors (SHRs) regulation and is related to many pathologic states and diseases such as stress-related disorder, cancer, metabolic syndrome, and chronic pain. FKBP51 acts on several cellular pathways likely through protein-protein interactions via its multifunctional domains. However, the functional basis of FKBP51 in signalling remains obscure due to the poor characterization of its biochemical properties. Importantly, the current FKBP51 inhibitors are not able to inactivate FKBP51 completely based on the occupancy-driven pharmacology. In this thesis, I synthesized a series of small molecules which aim to degrade FK506 binding proteins (FKBPs) via the recently developed proteolysis targeting chimera (PROTAC) strategy. A PROTAC is a heterobifunctional molecule consisting of a ligand for the target protein and a ligand for an E3 ligase, which induces the proteasomal degradation of the target protein. Unlike classical small molecule drugs, PROTACs intend to eliminate the aberrantly functioning protein rather than to inhibit it. By utilizing a selective FKBP51 ligand and non-selective FKBPs ligands developed by our group, two series of PROTACs were designed and synthesized. All of the selective SAFit-PROTACs showed affinities in the nanomolar range for FKBP51, while retaining high selectivity over the close homologue FKBP52. The degradation of cellular FKBP51 was observed upon treatment with the PROTAC MTQ202. In turn, I explored rigidified linkers based on MTQ202 to afford more potent PROTACs. The bicyclic ligand-based PROTACs exhibited outstanding affinities for all of the tested FKBPs in the low nanomolar range to subnanomolar range. The most potent compound, MTQ509, showed the highest binding affinity for FKBP51 so far reported (Ki = 0.92 nM).