Felix Hausch is professor for structure-based drug research at the Technical University Darmstadt. He is a recognized expert for the chemical biology of immunophilins (mainly FKBPs) and has discovered the SAFit class of selective FKBP51 ligands. He has authored 82 publications (incl. Nat Chem Biol, Angew Chem, JACS; h-factor= 34 (Google Scholar)) and >10 accepted patent families. He is speaker of the LOEWE consortium TRABITA, Core team member of the Zukunftscluster PROXIDRUGS, coordinator of the BMBF consortia iMIP and 51TaValP, co-coordinator of the VIP+ consortium Fit4Fat and of the ANR/BMBF consortium SIAM. Felix Hausch received his PhD from the Free University Berlin in 2000, gained postdoc experience at Stanford University and biotech industry in Zurich (ESBATech AG, 2 years), and was group leader at the Max-Planck Institute of Psychiatry and lecturer at the LMU (Munich, 2005-2016).
De novo identification of a fully synthetic FKBP12-FRB Molecular Glue
The gain-of-function pharmacology of Molecular Glues, prominently exemplified by the immunosuppressants FK506 and Rapamycin, holds great potential to address otherwise intractable targets. So far, the known Molecular Glues have been largely discovered by serendipity or in a target-agnostic manner. To explore the probability for the existence of Molecular Glues, we performed a targeted screen for Molecular Glues for FKBP12-FRB( FKBP-Rapamycin binding domain of mTOR), using Rapamcin as an established control. From our in-house FKBP-targeted ligand library, we identified a weak hit, that was validated in an FP-based secondary assay. Surprisingly, the structure of the ternary complex revealed a new binding mode of this hit compared to Rapamycin, which allow chemical optimization resulting in a fully synthetic FBKP12-FRB Molecular Glue with sub-micromolar efficacy. Our results show that with a focused library and a tailored assay cascade a targeted de-novo screening for Molecular Glues is feasible.
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