Abstract
BackgroundBruton’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.MethodsThe 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).ResultsHM71224 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.ConclusionsHM71224 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 materialThe online version of this article (doi:10.1186/s13075-016-0988-z) contains supplementary material, which is available to authorized users.
Highlights
Bruton’s tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells
HM71224 is a potent and selective inhibitor of Btk To determine the biochemical selectivity of HM71224, we tested more than 85 kinases using the fluorescence resonance energy transfer (FRET) method
Biotinylated probe bound to free Btk in a dose-dependent manner; approximately 90 % of Btk molecules were occupied by HM71224 at 10 nM, and close to 100 % at 100 nM (Fig. 2c)
Summary
Bruton’s tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. Park et al Arthritis Research & Therapy (2016) 18:91 cell activation might be of particular utility for the treatment of RA. Bruton’s tyrosine kinase (Btk) is involved in BCR signaling during B cell activation [6]. Following BCR engagement, Src family kinases activate Btk, which phosphorylates phospholipase-Cγ2 (PLCγ2), leading to calcium mobilization and activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinase pathways [7]. Btk (a member of the Tec kinase family) is involved in IC-mediated activation of monocytes and macrophages via Fcγ receptor (FcγR) binding. After binding to ICs, FcγRs activate Src kinases via the intracytoplasmic immunoreceptor tyrosine-based activation motif [9, 10]. Btk is involved in monocytederived osteoclast formation [11, 12]
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