Recent Progress in FKBP Ligand Development

FK506-binding proteins have been implicated in numerous human diseases suggesting novel therapeutic opportunities. In particular, the large FKBP51 has emerged as an important regulator of the stress-coping system and as an established risk factor for stress-related disorders. The principal druggabilty of FKBPs is evidenced by the prototypical high affinity ligands FK506 and rapamycin but the development of more refined and selective chemical probes for FKBPs has been challenging. In this review we summarize recent advances in the development of FKBP ligands, which cumulated in the first highly selective ligands for FKBP51. The best ligand SAFit2 allowed the proof-of-concept in mice for FKBP51 inhibitors as potentially novel antidepressants. Finally, we discuss pending issues that need to be addressed for the further development of FKBP51-directed drugs.