FKBP51-assisted GR- and AR-Targeting Molecular Glues (51-GR/AR Glues)

• Applicant: Professor Dr. Felix Hausch
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433472263

The glucocorticoid receptor (GR) and the androgen receptor (AR) are master regulators of several crucial endocrine processes and are key drug targets for the treatment of inflammation or prostate cancer. Both receptors are regulated in an intracellular feedback loop by the FK506-binding protein 51, which is strongly induced by glucocorticoids and androgens. FKBP51 (encoded by the FKBP5 gene) interacts with GR and AR as a part of the Hsp90 machinery. FKBP51 also has a ligand binding pocket that binds to the natural product FK506 and synthetic derivatives thereof. We and others recently elucidated the architecture of the FKBP51-Hsp90-GR complex and showed that the FK506-binding pocket of FKBP51 is close but not in direct contact with GR. Here we propose to develop FKBP51 ligands with a gain of function, which can form attractive or even covalent interactions with GR or AR in the context of the FKBP51-Hsp90-GR/AR complex. The compounds are expected to reinforce the endogenous function of FKBP51 as a GR-induced GR repressor or to pharmacologically reprogram FKBP51 from an AR-induced enhancer to an AR-induced repressor. Compared to traditional GR or AR antagonists these new modalities will act preferentially in cell types with high FKBP51 expression such as immune and prostate cancer cells. This offers unprecedented pharmacological means to manipulate steroid hormone receptors. In addition, it can provide a powerful showcase how molecular proximity-based drugs can enable a cell-type preferring pharmacology.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Privatdozent Dr. Martin Puhr, Ph.D.
• Co-Investigator: Professorin Dr. Marily Theodoropoulou