Pharmacological Exploration of the FK506-Binding Proteins 51 and 52 using PROTACs

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The FK506-binding protein 51 (FKBP51) and its counterplayer FKBP52 are key regulators of endocrine responses in mammals and are potential therapeutic targets for stress-related disorder, metabolic diseases, hormone-related cancers, and chronic pain. Recently, we developed the first selective inhibitors directed to the FK506-binding site of FKBP51, which have substantially increased our understanding of FKBP51. However, selective pharmacological tools for FKBP52 are still lacking. FKBP51 and FKBP52 are both multi-domain proteins and a key pending biochemical question is, which domains are responsible for the observed (molecular)biological effects (i.e. FK506-binding site vs scaffolding functions of other parts of the proteins).The goal of this chemical-biological project is to synthesize FKBP ligands based on the recently developed PROTAC technology, which allow chemically induced intracellular degradation of FKBP51 or FKBP52 in advanced model systems.(i) The prime objective for FKBP51 is to clarify, which effects of FKBP51 are mediated by the FK506-binding site and which by other parts of the protein. Specifically, we aim to show that FKBP51 degradation, but not inhibition, blocks the effect of FKBP51 on the glucocorticoid receptor (GR), on NF-kB signalling and on the kinase Akt. (ii) For FKBP52, the prime objective is to allow for the first time to pharmacologically differentiate against FKBP51. Specifically, we aim to show that pharmacological manipulation of FKBP52 allows to attenuate neurite outgrowth, GR and AR signaling and prostate cancer cell progression. With FKBP51- and FKBP52-selective probes both in hand, we will specifically explore the interplay between these two proteins. (iii) For the enhancement of PROTAC efficiency, our objective is to stabilize preferred linker conformations by site-specific introduction of methyl side chain substitutions in the oligoethylene glycol backbone. Specifically, we will develop a method for the rapid regio- and stereo-selective synthesis of ethylene/propylene glycol co-oligomers. The results of this proposal will provide fundamentally novel tools to explore human FK506-binding proteins and will clarify important pending questions for FKBP51 and FKBP52. In the PROTAC field, the expected findings would be the so far most compelling evidence that chemically induced protein degradation allows to hit otherwise intractable protein functions. The linker optimization strategy will be a general approach to improve efficacy of functional bioconjugates and of PROTACs in particular.