Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists

Retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of ROR gamma t is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 63; no. 1; pp. 241 - 259
Main Authors: Meijer, Femke A., Doveston, Richard G., de Vries, Rens M. J. M., Vos, Gael M., Vos, Alex A. A., Leysen, Seppe, Scheepstra, Marcel, Ottmann, Christian, Milroy, Lech-Gustav, Brunsveld, Luc
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 09.01.2020
Subjects:
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
PHASE
INTERFACE
ACCURATE DOCKING
MODULATORS
ALPHA
DIFFERENTIATION
ANTAGONISTS
DISCOVERY
PROGRAM
NUCLEAR RECEPTOR
ISSN:0022-2623, 1520-4804, 1520-4804
Online Access:Get more information
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Summary:Retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of ROR gamma 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 gamma 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 EM cells, a marker of ROR gamma t activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the ROR gamma 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 gamma t.
Bibliography:Marie Curie Actions (MSCA)
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content type line 23
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.9b01372