A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis
© 2020. The Author(s), under exclusive licence to CPS and SIMM..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:42 |
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| Enthalten in: |
Acta pharmacologica Sinica - 42(2021), 10 vom: 01. Okt., Seite 1653-1664 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Yu-Ting [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.01.2022 Date Revised 26.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41401-020-00578-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Liu, Yu-Ting |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis |
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| 500 | |a Date Revised 26.02.2024 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020. The Author(s), under exclusive licence to CPS and SIMM. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a B cells | |
| 650 | 4 | |a BTK inhibitors | |
| 650 | 4 | |a RANKL | |
| 650 | 4 | |a SOMCL-17-016 | |
| 650 | 4 | |a macrophages | |
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| 650 | 4 | |a rheumatoid arthritis | |
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| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a Pyrrolizidine Alkaloids |2 NLM | |
| 650 | 7 | |a Receptor Activator of Nuclear Factor-kappa B |2 NLM | |
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| 700 | 1 | |a Wang, Que |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shuang-Shuang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xiao-Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Feng-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yue-Teng |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Shi-Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Fang-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Zi-Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Geng, Mei-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ao |e verfasserin |4 aut | |
| 700 | 1 | |a He, Shi-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Zuo, Jian-Ping |e verfasserin |4 aut | |
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