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

作者：Anjaneya Chimalakonda, James R. Burke, Lihong Cheng, Ian M. Catlett, Michael Tagen, Qihong Zhao, Aditya Patel, Jun Shen, Ihab Girgis, Subhashis Banerjee, John Throup · 发表于：Dermatology and Therapy · 年份：2021 · DOI：10.1007/s13555-021-00596-8 · 被引用次数：134 · 研究领域：Cytokine Signaling Pathways and Interactions、Psoriasis: Treatment and Pathogenesis、Melanoma and MAPK Pathways

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. 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 (IC50) in these assays were determined for deucravacitinib and the JAK 1/2/3 inhibitors tofacitinib, upadacitinib, and baricitinib. Newly derived whole blood IC50 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 IC50 were evaluated. At clinically relevant exposures, projected steady-state deucravacitinib plasma concentrations were higher than TYK2 IC50 for approximately 9–18 h. Maximal plasma concentrations (Cmax) of deucravacitinib were 8- to 17-fold lower than JAK 1/3 IC50 and > 48- to > 102-fold lower than JAK 2/2 IC50. Simulated daily average TYK2 inhibition by deucravacitinib ranged from 50% to ...