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

Abstract

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.

Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors

“…However, the linker functionalization seemed to restore weak binding to FKBP52 for several macrocycles (e.g., 61a , 63 , and 64a ). Moreover, a slight preference for FKBP51 over FKBP12 and FKBP12.6 was observed, similar to previous findings for acyclic SAFit analogues. ,,,, This preference seems to be somewhat stronger for the para -linked series than for the meta -linked series.…”

“…Moreover, a slight preference for FKBP51 over FKBP12 and FKBP12.6 was observed, similar to previous findings for acyclic SAFit analogues. 20,28,33,34,52 This preference seems to be somewhat stronger for the para-linked series than for the meta-linked series.…”

“…We used existing 3D information on high-affinity inhibitors in a complex with the FK1 domain of FKBP51 to identify promising attachment points for the design of macrocyclic SAFit analogues. The crystal structures of known, selective FKBP51 inhibitors served as templates for our structure-based rigidification strategy. ,,,, SAFit analogues contain two aryl rings (A and B, Figure A), which are consistently in close proximity when bound to FKBP51, as illustrated for the FKBP51-SAFit2 complex (PDB 6TXX, Figure B). Structural analysis suggested the meta - or para -position of ring A and the meta -position of ring B as possible attachment points for linkers and modeling led us to postulate that macrocyclization within this structural framework would lead to macrocyclic ligands that could maintain all the binding interactions observed for the existing acyclic analogues.…”

“…Synthesis of Macrocyclic FKBP51 Ligands. The precursors for the para-(9−12) and the meta-series (27− 30) were cyclized via ring-closing metathesis to give the macrocycles (31)(32)(33)(34)(35)(36)(37)(38)Scheme 3). The ring-closing metatheses always afforded mixtures of E/Z-alkene isomers, except for 35 and the longest linker of each series (34 and 38), where only the E-alkenes were observed.…”

“…The recent discovery of the first FKBP51-selective ligands (SAFit1 and SAFit2) provided powerful tools to study the role of FKBP51 in cellular and animal models. ,,,− A newly discovered transient binding pocket is the key to selectivity for FKBP51 over the highly homologous FKBP52. ,− Nevertheless, SAFit1 and SAFit2 are far from becoming drug candidates due to their high molecular weight and the associated poor physicochemical properties . Additionally, the binding site of FKBP51 is shallow and the creation of low molecular mass inhibitors with high ligand efficiency and sufficient potency is extremely challenging. ,− …”