Nonreceptor tyrosine kinases, such as Bruton's tyrosine kinase (Btk), regulate the signal transduction of the B-cell antigen (BCR) and Fc (FcR) receptors that are critical in the development of rheumatoid arthritis (RA); therefore, pharmacological inhibition may affect multiple steps in the pathogenesis of RA and represent a useful therapeutic approach. The study by Xu et al. characterized the role of Btk using the novel, selective Btk inhibitor RN486 [6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one] in rodent and in vitro models of immune hypersensitivity and arthritis. The selective Btk inhibitor RN486 blocked BCR- and FcR-mediated biological and immune responses in both human cellular assays (tumor necrosis factor αproduction and CD69 expression) and rodent models (type I and III hypersensitivity), providing evidence for mechanism-based actions relevant to human diseases. RN486 produced robust efficacy in two standard rodent models of RA at concentrations that effectively block immunoreceptor-mediated pharmacodynamic responses, expression of CD69 in mice and PCA in rats. Together, these data show that Btk is a key regulator of immunoreceptor-mediated responses in both rodents and humans. Because these immunoreceptor-mediated responses are conserved between rodents and humans, and are essential for the development of immune arthritis in both species, they suggest clinical relevance and support the development of selective Btk inhibitors as RA therapeutics.

See article at J Pharmacol Exp Ther 2012, 341:90–103.

• Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics