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

doi:10.1038/s41401-020-00578-0

	A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis
	Liu, Yu-ting 2,3; Ding, Hui-hua 4; Lin, Ze-min 2; Wang, Que 2,5; Chen, Li 2,3; Liu, Shuang-shuang 2,3; Yang, Xiao-qian 2,3; Zhu, Feng-hua 2,3; Huang, Yue-teng 2,5; Cao, Shi-qi 2,3
刊名	ACTA PHARMACOLOGICA SINICA
	2021-01-13
页码	12
关键词	rheumatoid arthritis BTK inhibitors B cells macrophages RANKL osteoclastogenesis
ISSN号	1671-4083
DOI	10.1038/s41401-020-00578-0
通讯作者	Zhang, Ao(aozhang@simm.ac.cn) ; He, Shi-jun(heshijun@simm.ac.cn) ; Zuo, Jian-ping(jpzuo@simm.ac.cn)
英文摘要	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 (Fc gamma R) 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-PLC gamma 2-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.
资助项目	Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020369] ; National Natural Science Foundation of China (NSFC)[81903882] ; National Science and Technology Major Project New Drug Creation and Manufacturing Program, China[2018ZX09711002-014-001]
WOS关键词	COLLAGEN-INDUCED ARTHRITIS ; TYROSINE KINASE INHIBITOR ; RECEPTOR ACTIVATOR ; DIFFERENTIATION ; MICE ; TEC ; AUTOANTIBODIES ; DESTRUCTION ; GENERATION ; MONOCYTES
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000607492200001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296097]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Ao; He, Shi-jun; Zuo, Jian-ping
作者单位	1.Chinese Acad Sci, Shanghai Inst Materia Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Rheumatol, Shanghai 200001, Peoples R China 5.Shanghai Univ Tradit Chinese Med, Lab Immunol & Virol, Shanghai 201203, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Materia Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China
推荐引用方式 GB/T 7714	Liu, Yu-ting,Ding, Hui-hua,Lin, Ze-min,et al. A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis[J]. ACTA PHARMACOLOGICA SINICA,2021:12.
APA	Liu, Yu-ting.,Ding, Hui-hua.,Lin, Ze-min.,Wang, Que.,Chen, Li.,...&Zuo, Jian-ping.(2021).A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis.ACTA PHARMACOLOGICA SINICA,12.
MLA	Liu, Yu-ting,et al."A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis".ACTA PHARMACOLOGICA SINICA (2021):12.