Ligand-based design of allosteric retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists

Femke A. Meijer, Richard G. Doveston, Rens M J M de Vries, Gaël M. Vos, Alex A.A. Vos, Seppe Leysen, Marcel Scheepstra, Christian Ottmann, Lech-Gustav Milroy, Luc Brunsveld (Corresponding author)

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Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt 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 RORγt inverse agonists with a distinct isoxazole chemotype. The most potent compound, 25, displayed sub-micromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and co-crystallization with the RORγt 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 RORγt.

Original languageEnglish
Pages (from-to)241-259
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number1
Early online date10 Dec 2019
Publication statusPublished - 9 Jan 2020


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