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

Zasocitinib (TAK-279) is an investigational, oral, highly selective, and potent allosteric TYK2 inhibitor. This study assessed the TYK2 inhibitory selectivity and potency of zasocitinib versus those of licensed TYK2 and Jak inhibitors. Binding affinities were determined using homogenous time-resolved fluorescence. In vitro concentration-percentage 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 percentage inhibition were determined to estimate half-maximal inhibitory concentration. Times above half-maximal inhibitory concentration and percentage daily inhibition were modeled from simulated clinical concentrations. Zasocitinib bound the TYK2 Janus homology 2 domain with an inhibitory constant of 0.0087 nM, demonstrating more than 1 millionfold selectivity over Jak1. Zasocitinib potently inhibited TYK2 signaling, with half-maximal inhibitory concentrations of 48.2 nM (95% confidence interval = 36.8-63.1 nM), 21.6 nM (95% confidence interval = 17.3-26.9 nM), and 57.0 nM (95% confidence interval = 44.2-73.4 nM) for IL-23-pSTAT3, type I IFN-pSTAT3, and IL-12-pSTAT4 pathways, respectively; zasocitinib showed no inhibition of Jak1/2/3. Simulated clinical concentrations of 30 mg zasocitinib once daily exceeded the TYK2 half-maximal inhibitory concentration 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.