FBKP51 as a paradigm for translation and academic drug discovery

The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) has repeatedly been associated genetically with numerous stress-related affective disorders. FKBP51 is a key player in an intracellular negative feedback loop which reduces the signalling of the glucocorticoid receptor. The physiological role of FKBP51 in stress biology is further supported by a glucocorticoid-hyposensitive primate animal model and by FKBP51-knockout mice. This talk will focus on the translation of these biological findings into an academic drug discovery program for FKBP51. Towards this aim, we first characterized FKBP51 on the molecular level to mechanistically validate the mode of inhibition. We further developed numerous biochemical assays and applied them to a high throughput screening of chemical libraries to identify novel FKBP51 inhibitors. In a parallel we co-crystallized FKBP51 with several small molecule ligands derived from the prototypic ligand FK506 to support a structure-based rational drug design. Using this approach we developed several compound series that inhibited FKBP51 with sub-micromolar affinity and selectivity compared to the related homolog FKBP52. These small molecules will be use to pharmacologically probe the role of FKBP51 in animal models to provide the proof of concept for FKBP51 as a drug target. They could also form the starting point for a further chemical optimization to achieve the physicochemical parameters that are necessary for a clinical candidate.