AT A GLANCE

A new study published in MedComm (2020) shows that a novel dual inhibitor, Wj1113, inhibits BTK/JAK3 signaling in vivo and alleviates arthritis in joints, suggesting its potential as a promising dual-target therapeutic candidate for rheumatoid arthritis (RA).¹

“RA is a chronic autoimmune disease characterized by joint inflammation and tissue damage, driven by dysregulated cytokine signaling and immune cell hyperactivation,” explain study authors Zhang et al. To date, previous research has confirmed that “Bruton's tyrosine kinase (BTK) mediates pathogenic B-cell activation and autoantibody production, while Janus kinase 3 (JAK3) orchestrates cytokine-driven inflammation through signal transducer and activator of transcription 5 (STAT5) phosphorylation, exacerbating macrophage and monocyte activation.”

In the present study, the authors introduce Wj1113, a novel dual inhibitor that blocks both BTK and JAK3, as a potential RA therapeutic.

“Monocytes play a crucial role in arthritis pathogenesis, with their activation and chemotaxis being tightly linked to JAK3 signaling,” the authors explain further. “Aberrant JAK3 activation can lead to excessive monocyte recruitment and activation, thereby aggravating joint inflammation.” As such, the authors first determined that Wj1113 effectively suppresses monocyte chemotaxis and modulates inflammatory cytokine expression in monocytes, suggesting its potential as a therapeutic candidate for arthritis. In vitro experiments also concluded that Wj1113 strongly inhibits both macrophage and B-cell activation, which the authors attribute to its modulation of relevant arthritis signaling pathways.

Finally, the authors observed that Wj1113 treatment dose-dependently reduced joint inflammation; macrophage infiltration; and levels of tumor necrosis factor-α, interleukin-6, anti-cyclic citrullinated peptide antibody, and rheumatoid factor while elevating those of anti-inflammatory interleukin-10 in a collagen-induced arthritis mouse model. In addition, histopathological and micro–computed tomography analyses confirmed attenuation of cartilage/bone erosion and synovial hyperplasia, demonstrating Wj1113's significant therapeutic impact on arthritis.

 “Mechanistically, Wj1113 inhibits BTK/JAK3 signaling in vivo and alleviates arthritis in joints,” the authors conclude. “Collectively, these findings establish Wj1113 as a promising dual-target therapeutic candidate for RA, addressing both B-cell and cytokine-driven pathogenic pathways.”

Reference

1.     Zhang C, Lai F, Gong H, et al. A novel dual Bruton's tyrosine kinase/Janus kinase 3 inhibitor Wj1113 and its therapeutic effects on rheumatoid arthritis. MedComm (2020). 2025;6(7):e70207.