Abstract
Rheumatoid arthritis (RA) is characterized by joint leukocyte infiltration, synovial inflammation and bone damage result from osteoclastogenesis. Bruton’s tyrosine kinase (BTK) is a key regulator of B cell receptor (BCR) and Fc gamma receptor (FcγR) signaling involved in the pathobiology of RA and other autoimmune disorders. SOMCL-17-016 is a potent and selective tricyclic BTK inhibitor, structurally distinct from other known BTK inhibitors. In present study we investigated the therapeutic efficacy of SOMCL-17-016 in a mouse collagen-induced arthritis (CIA) model and underlying mechanisms. CIA mice were administered SOMCL-17-016 (6.25, 12.5, 25 mg·kg−1·d−1, ig), or ibrutinib (25 mg·kg−1·d−1, ig) or acalabrutinib (25 mg·kg−1·d−1, ig) for 15 days. We showed that oral administration of SOMCL-17-016 dose-dependently ameliorated arthritis severity and bone damage in CIA mice; it displayed a higher in vivo efficacy than ibrutinib and acalabrutinib at the corresponding dosage. We found that SOMCL-17-016 administration dose-dependently inhibited anti-IgM-induced proliferation and activation of B cells from CIA mice, and significantly decreased anti-IgM/anti-CD40-stimulated RANKL expression in memory B cells from RA patients. In RANKL/M-CSF-stimulated RAW264.7 cells, SOMCL-17-016 prevented osteoclast differentiation and abolished RANK-BTK-PLCγ2-NFATc1 signaling. In summary, this study demonstrates that SOMCL-17-016 presents distinguished therapeutic effects in the CIA model. SOMCL-17-016 exerts a dual inhibition of B cell function and osteoclastogenesis, suggesting that it to be a promising drug candidate for RA treatment.
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Acknowledgements
This work was supported by the Personalized Medicines—Molecular Signature-based “Drug Discovery and Development,” Strategic Priority Research Program of the Chinese Academy of Sciences (grant No. XDA12020369); the National Natural Science Foundation of China (NSFC) (grant No. 81903882); and the National Science and Technology Major Project “New Drug Creation and Manufacturing Program,” China (grant No. 2018ZX09711002-014-001).
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YTL, HHD, AZ, SJH, and JPZ contributed to the conception and design of this study; YTL and ZML completed the main part of the experiment; QW, LC, XQY and FHZ participated in the in vivo experiment; HHD, SSL, YTH, SQC, FMY participated in the in vitro experiment; ZLS contributed to the synthesis of the compound; AZ, SJH, JPZ, JD, MYG and HX contributed to drafting the paper and revising it critically for important intellectual content; and all authors contributed to this paper.
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Liu, Yt., Ding, Hh., Lin, Zm. et al. A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis. Acta Pharmacol Sin 42, 1653–1664 (2021). https://doi.org/10.1038/s41401-020-00578-0
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DOI: https://doi.org/10.1038/s41401-020-00578-0
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