FKBP ligands

Abstract

The FK-506 binding proteins 51 and 52 are co-chaperons that modulate in the signal transduction of the glucocorticoid receptor. Single nucleotide polymorphisms in the gene encoding FKBP51 have been shown to be associated with a variety of psychiatric disorders. The aim of our project is to develop selective inhibitors for these two proteins, which share 75% sequence similarity, but affect steroid hormone signal transduction in an opposing manner. Rapamycin and FK506 are two macrocyclic natural products, which bind to FKBP members with nanomolar affinity with little or no selectivity. A three-dimensional alignment of FKBP51, 52 and 12 structures revealed a structural divergence at the 80s loop. Hence an optimization of interaction with this part of the protein has the highest likelihood of achieving selectivity within the FKBP family. To address the selectivity and affinity problem we envisaged a strategy to synthesize small molecule analogs of FK506 and rapamycin bearing a variety of substituents that are expected to interact with the 80s loop. A focused solid support library synthesis was developed yielding compounds with low nanomolar binding affinity for FKBP12, and sub micromolar binding to FKBP51 and low micromolar affinity for FKBP52. Co-crystal structures of representative FKBP ligands were solved by X-ray crystallography to confirm the hypothesized binding mode.