Deucravacitinib

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of kinases, which are intracellular tyrosine kinases that activate the JAK–signal transducer and activator of the transcription pathway. Unlike other members of the JAK family that promote broader immune and extra-immune pathways, such as lipid metabolism, the TYK2 signalling pathway is responsible for selected immune pathways. TYK2 mediates the signalling of inflammatory cytokines of both adaptive (e.g., interleukin (IL) 12 and IL-23) and innate (e.g., type I interferons) immune responses. IL-23 has been implicated in the pathogenesis of immune-mediated disorders such as psoriasis and psoriatic arthritis. It activates and promotes the proliferation of Th17 cells: subsequently, Th17 cells secrete inflammatory mediators, such as IL-17 and tumour necrosis factor-alpha, that stimulate epidermal cells to produce cytokines and chemokines that attract and activate innate immune system cells. Enhanced activity of Th17 cells leads to sustained inflammatory responses in the skin and joints as manifested in psoriatic arthritis.

Deucravacitinib inhibits TYK2 via an allosteric mechanism: it binds to the enzyme's regulatory domain - also known as the pseudokinase (JH2) domain - instead of the catalytic domain. This binding activity allows high selectivity towards TYK2 over other tyrosine kinase enzymes. In in vitro cellular assays, deucravacitinib showed a 100-fold to 2000-fold selectivity for TYK2 over JAK 1/2/3 and demonstrated minimal or no activity against JAK 1/2/3. Upon binding to TYK2, deucravacitinib induces a conformational change and locks the regulatory domain of TYK2 into an inhibitory confirmation with the catalytic domain, trapping TYK2 in an inactive state. Inhibiting TYK2 leads to the downregulation of the IL-23/TH17 pathway, IL-12 signalling, type 1 interferon pathway, and keratinocyte activation.