Inhibition of Interleukin-23-Mediated Inflammation with a Novel Small Molecule Inverse Agonist of ROR γ t

Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of...

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Bibliographic Details
Published in:	The Journal of pharmacology and experimental therapeutics Vol. 371; no. 1; p. 208
Main Authors:	Gauld, Stephen B, Jacquet, Sebastien, Gauvin, Donna, Wallace, Craig, Wang, Yibing, McCarthy, Richard, Goess, Christian, Leys, Laura, Huang, Susan, Su, Zhi, Edelmayer, Rebecca, Wetter, Joseph, Salte, Katherine, McGaraughty, Steven P, Argiriadi, Maria A, Honore, Prisca, Luccarini, Jean-Michel, Bressac, Didier, Desino, Kelly, Breinlinger, Eric, Cusack, Kevin, Potin, Dominique, Kort, Michael E, Masson, Philippe J
Format:	Journal Article
Language:	English
Published:	United States 01-10-2019
Subjects:	Animals Anti-Inflammatory Agents - pharmacology Anti-Inflammatory Agents - therapeutic use Arthritis - drug therapy Cells, Cultured Chlorocebus aethiops COS Cells Female Humans Interleukin-23 - metabolism Male Mice Mice, Inbred C57BL Mice, Inbred DBA Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism Piperidines - pharmacology Piperidines - therapeutic use Psoriasis - drug therapy
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Summary:	Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) t and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoromethyl)-1H-indol-2-yl)methyl)benzoyl)piperidine-4-carboxylic acid (A-9758) was optimized from material identified from a high-throughput screening campaign. A-9758 is selective for ROR t and exhibits robust potency against IL-17A release both in vitro and in vivo. In vivo, we also show that IL-23 is sufficient to drive the accumulation of ROR t cells, and inhibition of ROR t significantly attenuates IL-23-driven psoriasiform dermatitis. Therapeutic treatment with A-9758 (i.e., delivered during active disease) was also effective in blocking skin and joint inflammation. Finally, A-9758 exhibited efficacy in an ex vivo human whole blood assay, suggesting small molecule inverse agonists of ROR t could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT: Using a novel small molecule inverse agonist, and preclinical assays, we show that ROR t is a viable target for the inhibition of ROR t/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of ROR t blocks both the accumulation and effector function of IL-17-producing T cells.
ISSN:	1521-0103
DOI:	10.1124/jpet.119.258046