Background/Purpose:  Tyk2 is a member of the JAK family kinases and is a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as lupus, psoriasis and inflammatory bowel diseases (IBD). Supported by compelling data from human genetic association studies, Tyk2 inhibition is an attractive therapeutic strategy for autoimmune diseases.

Methods:  We utilized cutting edge proprietary structure-based drug design tools to identify highly selective Tyk2 inhibitors. These inhibitors were characterized for their potency and selectivity in enzyme and cell-based assays, and in mouse models of IBD and psoriasis.

Results:  We have identified NDI-031407, a small molecule inhibitor of Tyk2, with potent enzyme and cellular activity, and excellent selectivity against other JAK family kinases and panels of receptors, transporters, ion channels, CYP enzymes and the hERG channel. This compound inhibits Tyk2 in a biochemical assay with a Ki of 0.2 nM, and is 218-, 148-, and 20-fold selective against JAK1, JAK2, and JAK3, respectively. Cell-based potency and selectivity of NDI-031407 was demonstrated in human PBMC assays by blockade of IL-12 induced phospho-STAT4, GM-CSF induced phospho-STAT5, and IL-2 induced phospho-STAT5, with IC₅₀ of 0.10 µM, 3.9 µM and 0.24 µM, respectively. In addition, NDI-031407 inhibited IL-12 induced IFNγ with IC₅₀ of 0.7 µM and 3.8 µM in human and mouse whole blood, respectively. We investigated the in vivo efficacy of NDI-031407 in mouse models of psoriasis and IBD. In an IL-23-induced mouse psoriasis model, NDI-031407 dose-dependently reduced disease with up to 74% inhibition of ear swelling and 96% inhibition of tissue levels of IL-17A at 100 mg/kg, highlighting the crucial role of Tyk2 inhibition in Th17 pathogenesis mediated by IL-23. In addition, NDI-031407 was highly efficacious in an imiquimod-induced mouse psoriasis model. NDI-031407 at 100 mg/kg achieved the same efficacy as dexamethasone in reduction of psoriasis score without body weight reduction. NDI-031407 treated mice had improved skin histology and dose-dependent reduction of spleen weight. To investigate the role of Tyk2 inhibition in Th1-driven pathogenesis, we tested NDI-031407 in a CD4⁺CD45RA⁺ adoptive transfer model that resembles the pathology of human Crohn’s disease. NDI-031407 treatment improved disease outcomes by reduction of body weight loss and colonic weight/length ratio, and improved colon histology. 100 mg/kg of NDI-031407 treatment also reduced colon myeloperoxidase levels to those of disease-free control mice, demonstrating the remarkable anti-inflammatory efficacy of Tyk2 inhibitors in this disease model.

Conclusion:  Utilizing unique and innovative structure-based drug design technologies, we rapidly designed highly selective and potent Tyk2 inhibitors with suitable pharmaceutical properties as potential therapeutics in inflammatory disorders. We validated the vital role of Tyk2 in disease pathogenesis of psoriasis and IBD in preclinical mouse models.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/potent-and-selective-tyk2-inhibitor-highly-efficacious-in-rodent-models-of-inflammatory-bowel-disease-and-psoriasis/