Why carry out this study?

The Janus kinase (JAK) and signal transducer and activator of transcription signaling pathways play major roles in intracellular cytokine signaling processes involved in the immune system and in the pathogenesis of various immune-mediated inflammatory diseases (IMIDs), as well as in non-immune functions such as hematopoiesis and lipid metabolism.

Several active-site-binding inhibitors of JAK 1/2/3 are approved or are in development for the treatment of IMIDs. However, these JAK inhibitors are associated with various non-immune-related adverse effects, including hematologic changes, hyperlipidemia, and renal and hepatic abnormalities, which may be due to the lack of selectivity of these inhibitors for specific family members.

A closely related intracellular kinase, tyrosine kinase 2 (TYK2), can pair with JAK 1 or JAK 2 in specific signaling pathways for cytokines such as type I interferons, interleukin (IL)-23, and IL-12. This analysis compared the functional selectivity of deucravacitinib (a novel, oral, allosteric, selective inhibitor of TYK2) versus approved inhibitors of JAK 1/2/3 (tofacitinib, upadacitinib, and baricitinib) for JAK 1/2/3 and TYK2 at clinically relevant doses and exposures.

What was learned from this study?

Simulations indicate that, at clinically relevant doses and exposures, deucravacitinib demonstrates functional inhibition solely of TYK2 and not JAK 1/2/3. In contrast, tofacitinib, upadacitinib, and baricitinib inhibit JAK 1, JAK 2, and/or JAK 3 to varying degrees but do not inhibit TYK2.

These results indicate that deucravacitinib is a distinct class of kinase inhibitor compared with inhibitors of JAK 1/2/3. The high functional selectivity for TYK2 coupled with the lack of inhibition of JAK 1/2/3 may contribute to an improved safety profile for deucravacitinib.