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

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posted on 07.05.2020, 11:21 by FA Meijer, RG Doveston, RMJM De Vries, GM Vos, AAA Vos, S Leysen, M Scheepstra, C Ottmann, LG Milroy, L Brunsveld
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 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 RORγt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization 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.

History

Citation

Journal of Medicinal Chemistry, 2020, 63, 1, 241-259

Author affiliation

Department of Chemistry

Version

VoR (Version of Record)

Published in

Journal of Medicinal Chemistry

Volume

63

Issue

1

Pagination

241 - 259

Publisher

American Chemical Society

issn

0022-2623

eissn

1520-4804

Acceptance date

10/12/2019

Copyright date

2019

Publisher version

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01372

Language

eng

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