Download MendeleyLigand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor gamma t (ROR gamma t) Inverse Agonists.
Meijer, F.A., Doveston, R.G., de Vries, R.M.J.M., Vos, G.M., Vos, A.A.A., Leysen, S., Scheepstra, M., Ottmann, C., Milroy, L.G., Brunsveld, L.(2020) J Med Chem 63: 241-259
- PubMed: 31821760
- DOI: https://doi.org/10.1021/acs.jmedchem.9b01372
- Primary Citation of Related Structures:
6SAL - PubMed Abstract:
Retinoic acid receptor-related orphan receptor ¦Ăt (ROR¦Ăt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of ROR¦Ăt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly efficient in silico-guided approach that led to the discovery of novel allosteric ROR¦Ăt inverse agonists with a distinct isoxazole chemotype. The the most potent compound, 25 ( FM26 ), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of ROR¦Ăt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the ROR¦Ăt ligand binding domain. The isoxazole compounds have promising pharmacokinetic properties comparable to other allosteric ligands but with a more diverse chemotype. The efficient ligand-based design approach adopted demonstrates its versatility in generating chemical diversity for allosteric targeting of ROR¦Ăt.
Organizational Affiliation:
Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems , Technische Universiteit Eindhoven , Den Dolech 2 , 5612 AZ Eindhoven , The Netherlands.
