Zasocitinib Effective in TYK2 Inhibition for Inflammatory Skin Disease: Study
Zasocitinib, billed as a 'next-generation' therapy, showed pharmacologic potency and high specificity compared to Janus and other kinase inhibitors, according to new results published in the Journal of Investigative Dermatology.
Researchers for the study used homogeneous time-resolved fluorescence and human whole blood assays to assess binding affinity and establish the cytokine inhibition profile of zasocitinib relative to other tyrosine kinase 2 (TYK2) and Janus kinase (JAK) inhibitors. Zasocitinib showed a TYK2 Janus homology 2 (JH2) domain inhibitory constant of 0.0087 nM, which exceeded the biochemical selectivity of deucravacitinib.
According to the study results, zasocitinib displayed inhibition across TYK2 inhibition pathways, with an IC50s of 48.2 nM for IL-23-pSTAT3, 21.6 nM for type I IFN-pSTAT3, and 57.0 nM for IL-12-pSTAT4, respectively. Simulated clinical plasma concentrations of zasocitinib 30 mg once daily maintained > 90% inhibition of TYK2 signaling for 24 hours with no impact on JAK1/2/3 signaling.
“In contrast to first-generation JAK inhibitors, which are associated with off-target effects and broad cytokine suppression, zasocitinib provides sustained and selective allosteric inhibition of TYK2, a critical mediator of IL-23, IL-12, and type I IFN pathways implicated in psoriasis pathogenesis,” the authors wrote. “This selectivity could reduce safety concerns linked to JAK1/2/3 inhibition while preserving anti-inflammatory efficacy.”
The researchers said the results suggest zasocitinib is effective as a 'next-generation' TYK2 inhibitor.
"The distinct, selective and sustained inhibition profile of zasocitinib, defines it as a next-generation TYK2 inhibitor that could potentially provide a more favorable benefit–risk profile than other oral inhibitors for IMIDs," the authors wrote. "The long-term safety and efficacy of zasocitinib are being assessed in ongoing phase 3 clinical trials in moderate-to-severe plaque psoriasis."
Source: Mehrotra S, et al. J Invest Dermatol. 2025. doi:10.1016/j.jid.2025.05.014