Selective BTK Inhibition by TAS5315: Effective Therapy in a Mouse Model of Rheumatoid Arthritis

Bruton's tyrosine kinase (BTK) plays a crucial role in various immune cells and is implicated in the pathogenesis of rheumatoid arthritis (RA). Targeting BTK could be a promising therapeutic strategy for RA. A novel and selective BTK inhibitor, TAS5315, has been synthesized and is under investigation for its potential in treating RA.

TAS5315 demonstrated high selectivity and potency in inhibiting BTK, with an IC50 in the sub-nanomolar range, and minimal off-target effects on 276 other kinases. It suppressed the activation of mouse splenic B cells, as indicated by the dose-dependent inhibition of CD69 up-regulation. Additionally, TAS5315 effectively inhibited osteoclast bone resorption activity in vitro.

In a mouse model of collagen-induced arthritis (CIA), TAS5315 administered orally showed significant dose-dependent improvements in clinical scores and completely resolved arthritic symptoms at the highest dose. Histopathological analysis revealed a marked reduction in inflammation, cartilage destruction, and bone erosion in TAS5315-treated mice. Micro-computed tomography (micro CT) analysis demonstrated a significant recovery of bone mineral density in these mice.

The study concludes that TAS5315 is a highly selective BTK inhibitor with significant efficacy in the CIA mouse model, suggesting its potential as a promising new therapeutic agent for RA. The researchers involved in this study are affiliated with Taiho Pharmaceutical Co., Ltd.