Selective Tyrosine Kinase 2 (TYK2) Inhibition in Plaque Psoriasis

The Janus kinase (JAK) family members, tyrosine kinase 2 (TYK2), JAK1, JAK2, and JAK3, are related nonreceptor tyrosine kinases that are associated with the cytoplasmic domains of cytokine receptors.^1,2 TYK2 solely mediates select immune functions; in contrast, JAK1,2,3 mediate broad systemic and immune functions (Figure 1).¹ JAK family members function predominantly as heterodimers and rarely as heterotrimers (JAK2 also functions as a homodimer), with specific pairings dictating their downstream effects.^1,2 The complex protein TYK2 has multiple domains, including a kinase or catalytic domain (also known as the Janus homology 1, or JH1, domain) and a pseudokinase or regulatory domain (also known as the JH2 domain), which lacks catalytic activity but plays an important role in regulating receptor-mediated activation of the catalytic domain via autoinhibitory interactions.^3,4

TYK2 is involved in a key axis of inflammation in psoriasis (Figure 2),⁵ mediating signaling by interleukin (IL)-12, IL-23, and Type I interferons (IFNs).^6-15 IL-23 stimulates T-helper 17 cells to produce IL-17, which then stimulates keratinocyte proliferation and epidermal hyperplasia. As other immune cells are attracted to the area, the inflammatory process is potentiated.⁵ Support for TYK2 playing a central role in the inflammatory process comes from TYK2 loss-of-function genetic mutations shown to be associated with a reduced risk of developing immune-mediated inflammatory diseases (IMIDs) such as psoriasis.¹⁶

The pathogenesis of psoriasis involves complex interactions among 1) proinflammatory cytokines, including IL-17, IL-23, IL-12, IL-19, tumor necrosis factor (TNF), and Type I IFNs (eg, IFN-alpha)^1,3; 2) immune cells, including T cells and dendritic cells³; and 3) keratinocytes.¹⁷ Some of these proinflammatory cytokines are regulated by JAK family members such as TYK2.^2,18 Extracellular binding of a cytokine to its receptor activates the associated intracellular JAK family members to activate signal transducers and activators of transcription

(STATs). Activated STATs dimerize and translocate from the cytoplasm to the nucleus to regulate the transcription of numerous target genes, resulting in increased expression of proinflammatory mediators such as IL-17.^1,2

Systemic treatment of moderate to severe plaque psoriasis with targeted therapies has focused primarily on direct inhibition of IL-17, IL-23, and TNF with biologic agents^1,17 and inhibition of phosphodiesterase-4.¹⁹ The monoclonal antibodies brodalumab, ixekizumab, bimekizumab, and secukinumab target IL-17; guselkumab, tildrakizumab, and risankizumab target IL-23; ustekinumab targets IL-12/23; and adalimumab, etanercept, infliximab, and certolizumab pegol target TNF-alpha, while the small molecule apremilast targets phosphodiesterase-4.^19,20 Targeting the JAK-STAT pathway is a current focus of research in dermatologic conditions. JAK1,2,3 inhibitors nonselectively bind to the adenosine 5'-triphosphate (ATP)-binding site on the catalytic domain of JAK1,2,3 and are not highly selective for any of the superfamily members, including TYK2.^21,22 JAK1,2,3 inhibitors are approved by the US Food and Drug Administration for use in dermatologic indications such as psoriatic arthritis, alopecia areata, atopic dermatitis, and vitiligo, as well as in additional disease states such as rheumatoid arthritis, ulcerative colitis, Crohn's disease, myelofibrosis, polycythemia vera, and graft versus host disease.²³