Development of specific inhibitors for the FK506 binding proteins 51 and 52

The FK506 binding proteins 51 and 52 act as cochaperones for Hsp90 to regulate the transactivational activity of steroid hormone receptors. Their role in mammalian endocrinology is supported by a primate animal model of FKBP51 over expression (Bolivian Squirrel Monkey) and FKBP52 knock-out mice displaying severe reproductive deficits. Furthermore, single nucleotide polymorphisms in the human gene encoding FKBP51 have repeatedly been associated with a variety of psychiatric disorders. To further characterize these FKBPs, specific inhibitors would be a valuable tool. Towards this end, we developed fluorescent tracers for the FK505 binding domain of FKBP51 and 52 and used them to screen a 40,000 compound chemical library. 65 new inhibitors, that could be clustered in three chemical scaffolds, where reproducibly identified. The best of these compounds inhibited FKBP51 with an IC50 of 1.2, 5.7 and 11µM. Importantly, these compounds exhibited 10-fold selectivity for FKBP51 vs. FKBP52 and might therefore be suitable to dissect the opposing action of these proteins on steroid hormone receptors.