TAS5315: A Selective BTK Inhibitor with Significant Efficacy in Collagen-Induced Arthritis in Mice

The text discusses the role of Bruton's tyrosine kinase (BTK) in various cell types and its involvement in rheumatoid arthritis (RA). It introduces TAS5315, a newly synthesized compound with high selectivity for BTK inhibition. The study aims to characterize TAS5315's effectiveness as a BTK inhibitor both in vitro and in an RA model.

The compound's selectivity was assessed through biochemical assays, and its impact on CD69 expression in mouse B cells was measured using flow cytometry. Additionally, TAS5315's effect on osteoclast bone resorption activity was evaluated using a culture kit. The study involved male DBA/1 mice, which were treated with complete Freund's adjuvant and bovine type II collagen to induce arthritis. TAS5315 was administered orally at varying doses for 15 days.

Results showed that TAS5315 was highly potent against BTK phosphorylation induced by anti-IgM and selectively inhibited four kinases out of 276 off-targets. It suppressed CD69 up-regulation in a dose-dependent manner and reduced osteoclast bone resorption activity. In a mouse model of collagen-induced arthritis, TAS5315 significantly decreased clinical scores and alleviated symptoms, with a dose-dependent reduction in inflammation, pannus, cartilage, and bone destruction. Micro CT analysis revealed a recovery of bone mineral density in TAS5315-treated mice.

The study concludes that TAS5315 is a highly selective BTK inhibitor with significant efficacy in a mouse model of RA, indicating its potential as a promising therapeutic agent for the treatment of RA.