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

Abstract
Introduction: Deucravacitinib is a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling. It works through an allosteric mechanism by binding to the enzyme’s regulatory domain, rather than the catalytic domain. This distinctive binding approach ensures high functional selectivity for TYK2, distinguishing it from the closely related Janus kinases (JAKs) 1/2/3. In phase 2 and 3 psoriasis trials, deucravacitinib showed efficacy without evidence of JAK 1/2/3 inhibition, either clinically or in laboratory parameters. This study compares the kinase selectivity of deucravacitinib to that of JAK 1/2/3 inhibitors at therapeutic exposure levels.

Methods: Signaling through JAK 1/3, JAK 2/2, and TYK2/JAK 2 dimers was assessed in in vitro whole blood assays. Half-maximal inhibitory concentrations (IC50) for deucravacitinib and the JAK 1/2/3 inhibitors tofacitinib, upadacitinib, and baricitinib were determined. Newly derived IC50 values from these whole blood assays were then plotted against available pharmacokinetic data from phase 2/3 trials. Simulations of daily average inhibition and the duration of time during which concentrations exceeded the IC50 were also performed.

Results: At clinically relevant exposures, the steady-state plasma concentrations of deucravacitinib remained above the TYK2 IC50 for approximately 9-18 hours. The maximal plasma concentrations (Cmax) of deucravacitinib were 8 to 17 times lower than the JAK 1/3 IC50 and over 48 to more than 102 times lower than the JAK 2/2 IC50. Simulated daily average TYK2 inhibition with deucravacitinib ranged from 50% to 69%. In comparison, tofacitinib, upadacitinib, and baricitinib showed varying degrees of JAK 1/3 inhibition (daily average, 70-94%) and JAK 2/2 inhibition (23%-67%) at therapeutic concentrations, with Cmax values 17 to 33 times lower than their respective TYK2 IC50 values.

Conclusion: Deucravacitinib, at clinically relevant doses, provides highly selective inhibition of TYK2 without affecting JAK 1/2/3. In contrast, tofacitinib, upadacitinib, and baricitinib primarily BMS-986165 inhibit JAK 1/2/3 and not TYK2. These findings suggest that deucravacitinib represents a distinct class of kinase inhibitor compared to traditional JAK 1/2/3 inhibitors.