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. Supported by compelling data from human genetic association studies, Tyk2 inhibition is an attractive therapeutic strategy for these diseases.

Methods: One of the challenges of developing selective Tyk2 inhibitors is the high sequence homology of the active site among the members of the JAK family kinases. We utilized cutting edge proprietary structure-based drug design tools to identify highly potent and selective inhibitors of Tyk2. These inhibitors were characterized for their potency and selectivity in the enzyme and cell-based assays, and in mouse models of delayed type hypersensitivity and psoriasis.

Results: We have identified Tyk2 inhibitors with up to 720-, 540-, and 210-fold selectivity against JAK1, JAK2, and JAK3 respectively, with potent cellular activity and excellent cellular selectivity against other JAK family kinases in human peripheral blood mononuclear cells. NDI-031301 is a Tyk2 inhibitor with a Ki of 0.5 nM that is 107-, 85-, and 15-fold selective against JAK1, JAK2, and JAK3 respectively. It blocks IL-12 induced phospho-STAT4 and GM-CSF induced phospho-STAT5 in human PBMCs with IC₅₀of 0.1 µM and 2.6 µM, respectively. NDI-031301 has excellent selectivity against a panel of 364 kinases, showing less than 70% inhibition at 300 nM against all but 16 of the kinases tested. It also showed less than 50% inhibition up to 30 µM against human CYP enzymes and hERG channel. In addition, NDI-031301 has an attractive PK profile with good oral bioavailability in rodents and dogs. Studies with humans carrying inactive forms of Tyk2 and mice deficient in Tyk2 revealed a role in Th1 and Th17 polarization. We investigated the in vivo activity and mechanism of action of Nimbus Tyk2 inhibitors in a methylated-BSA induced mouse delayed type hypersensitivity model. At 100 mg/kg dose, orally administered NDI-031301 reduced paw swelling and paw weight, as well as Th1 (IFNγ) and Th17 (IL-17A and IL-22) cytokines in the inflamed paws by more than 50%. It also dramatically reduced Th1 cells in the draining lymph nodes and suppressed over 85% of in vitro antigen-induced IFNγ response in the draining lymph node cells. In an IL-23-induced mouse psoriasis model, NDI-031301 dose-dependently reduced skin inflammation with up to 76% inhibition of ear swelling at 100 mg/kg, highlighting the role of Tyk2 inhibition in Th17 pathogenesis. Finally, NDI-031301 was highly efficacious in an imiquimod-induced mouse psoriasis model, showing dose-dependent reduction of psoriasis score, spleen weight, and improved skin histology. 30 mg/kg of NDI-031301 treatment blocked disease progression and 100 mg/kg treatment reversed the disease.

Conclusion: Utilizing unique and innovative structure-based drug design technologies, we rapidly designed highly potent and selective Tyk2 inhibitors for use as potential therapeutics in inflammatory disorders involving Th1, Th17, and type I interferon pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/potent-and-selective-tyk2-inhibitors-block-th1-and-th17-mediated-immune-responses-and-reduce-disease-progression-in-rodent-models-of-delayed-type-hypersensitivity-and-psoriasis/