Comparative Analysis Positions Zasocitinib Among Next-Generation TYK2 Inhibitors

Tyrosine kinase 2 (TYK2) is a key intracellular signaling mediator within the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway and plays an important role in immune-mediated inflammatory diseases (IMIDs), including psoriasis and psoriatic arthritis.¹ Therapeutic interest in TYK2 has increased following genetic and clinical evidence demonstrating that selective modulation of TYK2-dependent pathways may reduce inflammation while avoiding some safety concerns associated with broader JAK inhibition. A recently published study in the Journal of Investigative Dermatology reports the pharmacological characterization of zasocitinib (TAK-279), an investigational oral allosteric TYK2 inhibitor, with a focus on its selectivity, potency, and modeled clinical exposure relative to other TYK2 and JAK inhibitors.²

Study Objectives and Methods

The primary objective of the study was to evaluate the inhibitory selectivity and potency of zasocitinib for TYK2 compared with the approved TYK2 inhibitor deucravacitinib and licensed JAK inhibitors (baricitinib, upadacitinib, and tofacitinib). Binding affinity to the TYK2 Janus homology 2 (JH2) pseudokinase domain and the JAK1 JH2 domain was measured using homogeneous time-resolved fluorescence assays. Functional activity was assessed in human whole-blood assays measuring cytokine-induced STAT phosphorylation across TYK2-dependent pathways (IL-23, IL-12, and type I interferon) and JAK1/2/3-dependent pathways.

In addition, pharmacokinetic simulations were used to model plasma concentration–time profiles at clinically relevant doses. These simulations allowed estimation of time above half-maximal inhibitory concentration (IC50), time above 90% inhibitory concentration (IC90), and percentage daily inhibition for TYK2 and JAK pathways.

Key Findings on Selectivity and Potency

Zasocitinib demonstrated very high biochemical selectivity for TYK2. The compound bound the TYK2 JH2 domain with a sub-nanomolar inhibitory constant (Ki 0.0087 nM) and showed no detectable binding to the JAK1 JH2 domain, translating to more than 1-million-fold selectivity. In contrast, deucravacitinib, while also binding TYK2 with high affinity, exhibited substantially lower selectivity over JAK1.

In functional whole-blood assays, zasocitinib potently inhibited TYK2-mediated signaling pathways. IC50 values ranged from approximately 20 to 60 nM across IL-23–, IL-12–, and type I interferon–stimulated STAT phosphorylation assays. Importantly, no measurable inhibition of JAK1, JAK2, or JAK3 signaling was observed for zasocitinib at concentrations up to 30,000 nM. Deucravacitinib demonstrated TYK2 inhibition but with lower potency in most assays and minimal, though detectable, JAK1/3 pathway inhibition at higher concentrations. As expected, the licensed JAK inhibitors showed strong inhibition of JAK1/2/3 pathways and comparatively limited TYK2 selectivity.

Modeled Clinical Exposure

Simulation modeling suggested that a once-daily 30 mg dose of zasocitinib maintained plasma concentrations above the TYK2 IC50 and IC90 thresholds for a full 24-hour dosing interval across all TYK2 assays evaluated. This translated into modeled daily TYK2 inhibition exceeding 90%, without reaching inhibitory thresholds for JAK1/2/3 signaling. In comparison, simulated exposure for deucravacitinib at its approved dose achieved partial and time-limited TYK2 inhibition, while JAK inhibitors showed sustained JAK pathway inhibition with limited TYK2 coverage.

Clinical Context and Interpretation

Investigators behind the study said the findings support the characterization of zasocitinib as a next-generation allosteric TYK2 inhibitor with a distinct pharmacological profile. By targeting the regulatory JH2 domain rather than the conserved catalytic JH1 domain, zasocitinib achieves high TYK2 selectivity, theoretically reducing the risk of adverse events associated with broader JAK inhibition. The sustained TYK2 pathway coverage observed in simulations aligns with early clinical trial data showing efficacy and a favorable short-term safety profile in patients with psoriasis and psoriatic arthritis.

However, the authors note several limitations. The study relied on in vitro assays and pharmacokinetic modeling rather than direct clinical pharmacodynamic measurements, and STAT phosphorylation was used as a surrogate for downstream immune effects. As with all early-phase pharmacological studies, the long-term clinical relevance of sustained TYK2 inhibition remains to be established in phase 3 trials.

Conclusion

This study provides a detailed comparative pharmacological assessment of zasocitinib, demonstrating high selectivity, potent TYK2 inhibition, and sustained modeled exposure without measurable JAK1/2/3 inhibition. These findings support continued clinical development of zasocitinib for IMIDs and contribute to the evolving understanding of selective TYK2 inhibition as a therapeutic strategy. Ongoing phase 3 trials will be essential to confirm whether these pharmacological advantages translate into durable clinical efficacy and long-term safety.

References

1. Rusiñol L, Puig L. Tyk2 Targeting in immune-mediated inflammatory diseases. Int J Mol Sci. 2023;24(4):3391. Published 2023 Feb 8. doi:10.3390/ijms24043391
2. Mehrotra S, Sano Y, Halkowycz P, et al. Pharmacological characterization of zasocitinib (TAK-279): An oral, highly selective, and potent allosteric TYK2 inhibitor. J Invest Dermatol. 2026;146(1):214-222.e7. doi:10.1016/j.jid.2025.05.014