Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor ?t (ROR?t) Inverse Agonists.

ABSTRACT: Retinoic acid receptor-related orphan receptor ?t (ROR?t) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of ROR?t 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?t 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?t activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the ROR?t 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?t.

SUBMITTER: Meijer FA 

PROVIDER: S-EPMC6956242 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature