Pharmacological Characterization of Zasocitinib (TAK-279): An Oral, Highly Selective and Potent Allosteric TYK2 Inhibitor.

Abstract

Zasocitinib (TAK-279) is an investigational, oral, highly selective and potent allosteric tyrosine kinase 2 (TYK2) inhibitor. This study assessed the TYK2 inhibitory potency and selectivity of zasocitinib versus licensed TYK2 and JAK inhibitors. Binding affinities were determined using homogenous time-resolved fluorescence. In vitro concentration-percent inhibition curves for IL-23-phosphorylated signal transducer and activator of transcription (pSTAT) 3, type I IFN-pSTAT3, IL-12-pSTAT4, IL-2-pSTAT5 and thrombopoietin-pSTAT3 pathways were established using human whole blood assays. Relationships between concentration and percent inhibition were determined to estimate half-maximal inhibitory concentration (IC₅₀). Time above IC₅₀ and percent daily inhibition were modeled from simulated clinical concentrations. Zasocitinib bound the TYK2 Janus homology 2 domain with a inhibitory constant of 0.0087nM, demonstrating more than 1 millionfold selectivity over JAK1. Zasocitinib potently inhibited TYK2 signaling, with IC₅₀s for IL-23-pSTAT3, type I IFN-pSTAT3 and IL-12-pSTAT4 of 48.2nM (95% confidence interval [CI]: 36.8-63.1nM), 21.6nM (95% CI: 17.3-26.9nM) and 57.0nM (95% CI: 44.2-73.4nM), respectively; zasocitinib showed no inhibition of JAK1/2/3. Simulated clinical concentrations of zasocitinib 30 mg once daily exceeded the TYK2 IC₅₀ for 24 hours, maintaining >90% daily inhibition, with no JAK1/2/3 inhibition. The distinct potent and selective inhibition profile of zasocitinib defines it as a next-generation TYK2 inhibitor.