Discovery of novel dual Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis.

ABSTRACT

Rheumatoid arthritis (RA) is a chronically systemic autoimmune disorder, which is related with various cellular signal pathways. Both BTK (Bruton's Tyrosine Kinase) and JAK3 (Janus Kinase 3) play important roles in the pathogenesis of rheumatoid arthritis. Herein, we reported the discovery of dual BTK/JAK3 inhibitors through bioisosterism and computer-aided drug design based on the structure of BTK inhibitor ibrutinib. We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, compound XL-12 (LD50 > 1600 mg/kg) exerted improved safety compared with ibrutinib (LD50 = 750 mg/kg). These results indicated that compound XL-12, the dual BTK/JAK3 inhibitor, might be a potent drug candidate for the treatment of RA.