Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors

Introduction Deucravacitinib, a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling, acts via an allosteric mechanism by binding to the enzyme’s regulatory domain instead of the catalytic domain. This unique binding provides high functional selectivity for TYK2 versus the closely related Janus kinases (JAKs) 1/2/3. Deucravacitinib was efficacious in phase 2 and 3 psoriasis trials, without clinical or laboratory parameters indicative of JAK 1/2/3 inhibition being observed. This analysis compared the kinase specificities of deucravacitinib versus JAK 1/2/3 inhibitors at therapeutic exposures. Methods Signaling via JAK 1/3, JAK 2/2, and TYK2/JAK 2 dimers was measured in in vitro whole blood assays. Concentrations providing half-maximal inhibition (IC 50 ) in these assays were determined for deucravacitinib and the JAK 1/2/3 inhibitors tofacitinib, upadacitinib, and baricitinib. Newly derived whole blood IC 50 values were plotted against available pharmacokinetic profiles using doses evaluated in phase 2/3 trials. Simulated average daily inhibition and durations over which concentrations exceeded IC 50 were evaluated. Results At clinically relevant exposures, projected steady-state deucravacitinib plasma concentrations were higher than TYK2 IC 50 for approximately 9–18 h. Maximal plasma concentrations ( C max ) of deucravacitinib were 8- to 17-fold lower than JAK 1/3 IC 50 and > 48- to > 102-fold lower than JAK 2/2 IC 50 . Simulated daily average TYK2 inhibition by deucravacitinib ranged from 50% to 69%. Simulations indicated that tofacitinib, upadacitinib, and baricitinib at steady state exhibited varying degrees of JAK 1/3 (daily average inhibition, 70–94%) and JAK 2/2 (23%–67%) inhibition at therapeutic concentrations, with C max values 17- to 33-fold lower than their TYK2 IC 50 levels. Conclusion At clinically relevant doses and exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 and not JAK 1/2/3. Tofacitinib, upadacitinib, and baricitinib variably inhibit JAK 1/2/3 but not TYK2. These results indicate that deucravacitinib is a distinct class of kinase inhibitor compared with JAK 1/2/3 inhibitors. Plain Language Summary Psoriasis is a common, chronic inflammatory skin condition that impairs patients’ physical health, emotional well-being, work performance, and overall quality of life. Psoriasis and related conditions such as psoriatic arthritis are caused by abnormalities in the immune system. Various drugs are u