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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

Cited 38 time in Web of Science Cited 29 time in Scopus
Authors
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
Issue Date
2016-04-18
Publisher
BioMed Central
Citation
Arthritis Research & Therapy, 18(1):91
Keywords
B cellsBtk inhibitorInflammationHM71224MonocytesRheumatoid arthritisOsteoclast
Abstract
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 (IC50 = 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.
Language
English
URI
http://hdl.handle.net/10371/109903
DOI
https://doi.org/10.1186/s13075-016-0988-z
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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