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HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis
BACKGROUND: Bruton’s tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis. METHODS: The kinase inhibition profile of HM71224 was anal...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835877/ https://www.ncbi.nlm.nih.gov/pubmed/27090981 http://dx.doi.org/10.1186/s13075-016-0988-z |
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author | Park, Jin Kyun Byun, Joo-Yun Park, Ji Ah Kim, Yu-Yon Lee, Ye Ji Oh, Jeong In Jang, Sun Young Kim, Young Hoon Song, Yeong Wook Son, Jeewoong Suh, Kwee Hyun Lee, Young-Mi Lee, Eun Bong |
author_facet | Park, Jin Kyun Byun, Joo-Yun Park, Ji Ah Kim, Yu-Yon Lee, Ye Ji Oh, Jeong In Jang, Sun Young Kim, Young Hoon Song, Yeong Wook Son, Jeewoong Suh, Kwee Hyun Lee, Young-Mi Lee, Eun Bong |
author_sort | Park, Jin Kyun |
collection | PubMed |
description | BACKGROUND: Bruton’s tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis. METHODS: The kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis (CIA). RESULTS: HM71224 irreversibly bound to and inhibited Btk (IC(50) = 1.95 nM). The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA. CONCLUSIONS: HM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-016-0988-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4835877 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-48358772016-04-20 HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis Park, Jin Kyun Byun, Joo-Yun Park, Ji Ah Kim, Yu-Yon Lee, Ye Ji Oh, Jeong In Jang, Sun Young Kim, Young Hoon Song, Yeong Wook Son, Jeewoong Suh, Kwee Hyun Lee, Young-Mi Lee, Eun Bong Arthritis Res Ther Research Article BACKGROUND: Bruton’s tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis. METHODS: The kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis (CIA). RESULTS: HM71224 irreversibly bound to and inhibited Btk (IC(50) = 1.95 nM). The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA. CONCLUSIONS: HM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-016-0988-z) contains supplementary material, which is available to authorized users. BioMed Central 2016-04-18 2016 /pmc/articles/PMC4835877/ /pubmed/27090981 http://dx.doi.org/10.1186/s13075-016-0988-z Text en © Park et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Park, Jin Kyun Byun, Joo-Yun Park, Ji Ah Kim, Yu-Yon Lee, Ye Ji Oh, Jeong In Jang, Sun Young Kim, Young Hoon Song, Yeong Wook Son, Jeewoong Suh, Kwee Hyun Lee, Young-Mi Lee, Eun Bong HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis |
title | HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis |
title_full | HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis |
title_fullStr | HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis |
title_full_unstemmed | HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis |
title_short | HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis |
title_sort | hm71224, a novel bruton’s tyrosine kinase inhibitor, suppresses b cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835877/ https://www.ncbi.nlm.nih.gov/pubmed/27090981 http://dx.doi.org/10.1186/s13075-016-0988-z |
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