6sal

Publication Abstract from PubMed

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

Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor gammat (RORgammat) Inverse Agonists.,Meijer FA, Doveston RG, de Vries RMJM, Vos GM, Vos AAA, Leysen S, Scheepstra M, Ottmann C, Milroy LG, Brunsveld L J Med Chem. 2019 Dec 24. doi: 10.1021/acs.jmedchem.9b01372. PMID:31821760^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.