2. Academic Validation
  3. Inhibition of Interleukin-23-Mediated Inflammation with a Novel Small Molecule Inverse Agonist of ROR γ t

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

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.) stephen.gauld@abbvie.com.
  • 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z