Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition

Abstract

PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Importantly, by sparing JAK1 function, PF-06651600 selectively targets γc cytokine pathways while preserving JAK1-dependent anti-inflammatory signaling such as the IL-10 suppressive functions following LPS treatment in macrophages and the suppression of TNFα and IL-1β production in IL-27-primed macrophages. Thus, JAK3-selective inhibition differentiates from pan-JAK or JAK1 inhibition in various immune cellular responses, which could potentially translate to advantageous clinical outcomes in inflammatory and autoimmune diseases.

Comparative efficacy of topical oclacitinib 0.1% and tacrolimus 0.01% in canine keratoconjunctivitis sicca

“…JAK1 and JAK3 have similar effects on cytokine signaling, however, JAK 3 expression is limited to hematopoietic cells . JAK1 is associated with a wider array of receptor chains and with a more widespread effect than JAK3 . Tofacitinib and oclacitinib inhibit JAK1/3 and thus prevent upregulation of interleukins involved in lymphocyte stimulation .…”

2017 White Paper on Recent Issues in Bioanalysis: Rise of Hybrid LBA/LCMS Immunogenicity Assays (Part 2: Hybrid LBA/LCMS Biotherapeutics, Biomarkers & Immunogenicity Assays and Regulatory Agencies’ Inputs)

“…This includes target measurements in normal versus disease matrices; however, obtaining accurate and robust measurements can be challenging. These challenges can come from many factors, such as binding partners, soluble or shed receptors, splice variants, post-translational modifications, just to name a few [21,22].…”

HiJAKing Innate Lymphoid Cells?

“…Molecules like decernotinib and PF-06651600 (JAK3 selective) are already in late-phase clinical development, but they are also useful tools to understand the biological role of JAK3 in ILCs. On the other hand, given that several of the cytokines mentioned above also signal through JAK1, compounds like filgotinib (JAK1 selective but with some activity on JAK2), upadacitinib, and PF-04965842 (JAK1 selective) could be very helpful to understand the biological role of each the JAKs (53). Interestingly, tofacitinib has shown promising results in the treatment of ulcerative colitis but a lack of efficacy in Crohn’s disease whereas filgotinib has shown some efficacy.…”