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

  • J Pharmacol Exp Ther. 2019 Oct;371(1):208-218. doi: 10.1124/jpet.119.258046.
Stephen B Gauld  1 ,  Sebastien Jacquet  1 ,  Donna Gauvin  2 ,  Craig Wallace  2 ,  Yibing Wang  2 ,  Richard McCarthy  2 ,  Christian Goess  2 ,  Laura Leys  2 ,  Susan Huang  2 ,  Zhi Su  2 ,  Rebecca Edelmayer  2 ,  Joseph Wetter  2 ,  Katherine Salte  2 ,  Steven P McGaraughty  2 ,  Maria A Argiriadi  2 ,  Prisca Honore  2 ,  Jean-Michel Luccarini  2 ,  Didier Bressac  2 ,  Kelly Desino  2 ,  Eric Breinlinger  2 ,  Kevin Cusack  2 ,  Dominique Potin  2 ,  Michael E Kort  2 ,  Philippe J Masson  2
Affiliations
  • 1. AbbVie Inc., North Chicago, Illinois (S.B.G., Y.W., L.L., S.H., Z.S., J.W., K.S., S.P.M., P.H., K.D., M.E.K., D.G., R.E.); Inventiva, Daix, France (J.-M.L., D.B., D.P., P.J.M., S.J.); and AbbVie Bioresearch Center, Worcester, Massachusetts (C.W., R.M., C.G., M.A.A., E.B., K.C.) [email protected].
  • 2. AbbVie Inc., North Chicago, Illinois (S.B.G., Y.W., L.L., S.H., Z.S., J.W., K.S., S.P.M., P.H., K.D., M.E.K., D.G., R.E.); Inventiva, Daix, France (J.-M.L., D.B., D.P., P.J.M., S.J.); and AbbVie Bioresearch Center, Worcester, Massachusetts (C.W., R.M., C.G., M.A.A., E.B., K.C.).
PMID: 31375639 DOI: 10.1124/jpet.119.258046
Abstract

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) γt 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 RORγt 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 RORγt+ cells, and inhibition of RORγt 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 RORγt could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT: Using a novel small molecule inverse agonist, and preclinical assays, we show that RORγt is a viable target for the inhibition of RORγt/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of RORγt blocks both the accumulation and effector function of IL-17-producing T cells.

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