Differences in JAK Isoform Selectivity Among Different Types of JAK Inhibitors Evaluated for Rheumatic Diseases Through In Vitro Profiling
Authors' conclusion
Inhibition of JAK kinase activity did not directly translate into cellular inhibition of JAK/STAT signaling. Despite differences in JAK selectivity, the cytokine inhibition profiles of currently approved Jakinibs were highly similar, with preference for JAK1-mediated cytokines. Novel types of Jakinibs showed narrow cytokine inhibition profile specific for JAK3- or TYK2-mediated signaling.
Study context
- Population
- Blood samples from healthy volunteers and isolated peripheral blood mononuclear cells (PBMCs) from patients with RA and from healthy donors10 Jakinibs analysed
- Comparison
- 10 JAK inhibitors profiled in parallel for JAK isoform and cytokine selectivity
- Outcome
- JAK isoform selectivity: inhibition of JAK kinase activity, binding to kinase and pseudokinase domains, and inhibition of cytokine signaling
Methodological detailsin vitro profiling, head-to-head parallel comparison
- In vitro profiling
- Head-to-head parallel comparison
Main finding
As reported in the abstract
Ritlecitinib (covalent): fold selectivity for JAK3 over other JAKs, with specific suppression of IL-2 signaling
900- to 2,500-fold
Original publication
Differences in JAK Isoform Selectivity Among Different Types of JAK Inhibitors Evaluated for Rheumatic Diseases Through In Vitro Profiling. Arthritis Rheumatol. Published 3 August 2023. doi:10.
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