Inhibition Of Interleukin-23-Mediated Inflammation With A Novel Small Molecule Inverse Agonist Of Ror Gamma 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-23/1L-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) gamma t and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoronnethyl)-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 gamma 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 gamma t(+) cells, and inhibition of ROR gamma 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 gamma t could be efficacious in human IL-17-related diseases.SIGNIFICANCE STATEMENTUsing a novel small molecule inverse agonist, and preclinical assays, we show that ROR gamma t is a viable target for the inhibition of ROR gamma t/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of ROR gamma t blocks both the accumulation and effector function of IL-17-producing T cells.