A Novel Decalin-Based Bicyclic Scaffold for FKBP51-Selective Ligands

Selective inhibition of FKBP51 has emerged as possible
novel treatment
for diseases like major depressive disorder, obesity, chronic pain,
and certain cancers. The current FKBP51 inhibitors are rather large,
flexible, and have to be further optimized. By using a structure-based
rigidification strategy, we hereby report the design and synthesis
of a novel promising bicyclic scaffold for FKBP51 ligands. The structure–activity
analysis revealed the decalin scaffold as the best moiety for the
selectivity-enabling subpocket of FBKP51. The resulting compounds
retain high potency for FKBP51 and excellent selectivity over the
close homologue FKBP52. With the cocrystal structure of an advanced
ligand in this novel series, we show how the decalin locks the key
selectivity-inducing cyclohexyl moiety of the ligand in a conformation
typical for FKBP51-selective binding. The best compound 29 produces cell death in a HeLa-derived KB cell line, a cellular model
of cervical adenocarcinoma, where FKBP51 is highly overexpressed.
Our results show how FKBP51 inhibitors can be rigidified and extended
while preserving FKBP51 selectivity. Such inhibitors might be novel
tools in the treatment of human cancers with deregulated FKBP51.