Plaque
psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The
Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular
cytokine signaling in inflammatory processes involved in
psoriasis. Although
Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe
psoriasis, safety concerns persist and no
JAK inhibitor has received regulatory approval to treat
psoriasis. Thus, an opportunity exists for novel oral
therapies that are safe and efficacious in
psoriasis.
Tyrosine kinase 2 (TYK2) is a member of the JAK family of
kinases and regulates signaling and functional responses downstream of the
interleukin 12,
interleukin 23, and
type I interferon receptors.
Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and
PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (
adenosine triphosphate-binding) site in the catalytic domain, are in development for
psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-
JAK inhibitors. This article reviews
Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of
JAK inhibitors in
psoriasis to date, focusing specifically on TYK2 inhibitors.