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A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis

   
@article{APS10406,
	author = {Yu-ting Liu and Hui-hua Ding and Ze-min Lin and Que Wang and Li Chen and Shuang-shuang Liu and Xiao-qian Yang and Feng-hua Zhu and Yue-teng Huang and Shi-qi Cao and Fang-ming Yang and Zi-lan Song and Jian Ding and Mei-yu Geng and Hua Xie and Ao Zhang and Shi-jun He and Jian-ping Zuo},
	title = {A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis},
	journal = {Acta Pharmacologica Sinica},
	volume = {42},
	number = {10},
	year = {2021},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10406}
}