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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.

Park JK, Byun JY, Park JA, Kim YY, Lee YJ, Oh JI, Jang SY, Kim YH, Song YW, Son J, Suh KH, Lee YM, Lee EB - Arthritis Res. Ther. (2016)

Bottom Line: 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.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.Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea.

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.

No MeSH data available.


Related in: MedlinePlus

Kinase selectivity of the Bruton’s tyrosine kinase (Btk) inhibitor, HM71224. a Kinome Binding Tree Spot analysis of HM71224 based on Scan Max data (DiscoveRx). HM71224 selectively bound to Btk (a TEC family kinase) at a concentration of 2 μM (indicated by red circles). b Selectivity of Btk for a screened panel of kinases. *TEC family kinase (TFK), EGFR epidermal growth factor receptor, JAK Janus kinase, BMX bone marrow kinase on chromsome X, TK tyrosine kinase, TKL tyrosine kinase-like, STE homolog of Sterile, CK1 Casein kinase 1, AGC protein kinase A, G, and C families, CAMK Ca2+/calmodulin-dependent protein kinase, CMGC cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK), CDK-like kinases, BLK B-cell lymphocyte kinase, ITK IL2-Inducible T-Cell Kinase, JAK3 Janus kinase 3, LCK lymphocyte-specific protein tyrosine kinase, CSK C-Src Tyrosine Kinase
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Fig1: Kinase selectivity of the Bruton’s tyrosine kinase (Btk) inhibitor, HM71224. a Kinome Binding Tree Spot analysis of HM71224 based on Scan Max data (DiscoveRx). HM71224 selectively bound to Btk (a TEC family kinase) at a concentration of 2 μM (indicated by red circles). b Selectivity of Btk for a screened panel of kinases. *TEC family kinase (TFK), EGFR epidermal growth factor receptor, JAK Janus kinase, BMX bone marrow kinase on chromsome X, TK tyrosine kinase, TKL tyrosine kinase-like, STE homolog of Sterile, CK1 Casein kinase 1, AGC protein kinase A, G, and C families, CAMK Ca2+/calmodulin-dependent protein kinase, CMGC cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK), CDK-like kinases, BLK B-cell lymphocyte kinase, ITK IL2-Inducible T-Cell Kinase, JAK3 Janus kinase 3, LCK lymphocyte-specific protein tyrosine kinase, CSK C-Src Tyrosine Kinase

Mentions: To determine the biochemical selectivity of HM71224, we tested more than 85 kinases using the fluorescence resonance energy transfer (FRET) method. As summarized in Fig. 1, HM71224 was highly selective for Btk: HM71224 inhibited Btk with an IC50 of 1.95 nM. HM71224 inhibited other kinases, including BMX, TEC, and TXK, which carry a conserved cysteine in the binding pocket (Additional file 1: Table S1). HM71224 had some inhibitory effect on the epidermal growth factor receptor (EGFR) in biochemical sense (Fig. 1b). However, more than 1000 nM of HM71224 was required to inhibit 50 % of cellular growth in EGFR-overexpressed A431 cells (Additional file 1: Figure S2A) or phosphorylation of EGFR (Additional file 1: Figure S2B).Fig. 1


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 JK, Byun JY, Park JA, Kim YY, Lee YJ, Oh JI, Jang SY, Kim YH, Song YW, Son J, Suh KH, Lee YM, Lee EB - Arthritis Res. Ther. (2016)

Kinase selectivity of the Bruton’s tyrosine kinase (Btk) inhibitor, HM71224. a Kinome Binding Tree Spot analysis of HM71224 based on Scan Max data (DiscoveRx). HM71224 selectively bound to Btk (a TEC family kinase) at a concentration of 2 μM (indicated by red circles). b Selectivity of Btk for a screened panel of kinases. *TEC family kinase (TFK), EGFR epidermal growth factor receptor, JAK Janus kinase, BMX bone marrow kinase on chromsome X, TK tyrosine kinase, TKL tyrosine kinase-like, STE homolog of Sterile, CK1 Casein kinase 1, AGC protein kinase A, G, and C families, CAMK Ca2+/calmodulin-dependent protein kinase, CMGC cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK), CDK-like kinases, BLK B-cell lymphocyte kinase, ITK IL2-Inducible T-Cell Kinase, JAK3 Janus kinase 3, LCK lymphocyte-specific protein tyrosine kinase, CSK C-Src Tyrosine Kinase
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835877&req=5

Fig1: Kinase selectivity of the Bruton’s tyrosine kinase (Btk) inhibitor, HM71224. a Kinome Binding Tree Spot analysis of HM71224 based on Scan Max data (DiscoveRx). HM71224 selectively bound to Btk (a TEC family kinase) at a concentration of 2 μM (indicated by red circles). b Selectivity of Btk for a screened panel of kinases. *TEC family kinase (TFK), EGFR epidermal growth factor receptor, JAK Janus kinase, BMX bone marrow kinase on chromsome X, TK tyrosine kinase, TKL tyrosine kinase-like, STE homolog of Sterile, CK1 Casein kinase 1, AGC protein kinase A, G, and C families, CAMK Ca2+/calmodulin-dependent protein kinase, CMGC cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK), CDK-like kinases, BLK B-cell lymphocyte kinase, ITK IL2-Inducible T-Cell Kinase, JAK3 Janus kinase 3, LCK lymphocyte-specific protein tyrosine kinase, CSK C-Src Tyrosine Kinase
Mentions: To determine the biochemical selectivity of HM71224, we tested more than 85 kinases using the fluorescence resonance energy transfer (FRET) method. As summarized in Fig. 1, HM71224 was highly selective for Btk: HM71224 inhibited Btk with an IC50 of 1.95 nM. HM71224 inhibited other kinases, including BMX, TEC, and TXK, which carry a conserved cysteine in the binding pocket (Additional file 1: Table S1). HM71224 had some inhibitory effect on the epidermal growth factor receptor (EGFR) in biochemical sense (Fig. 1b). However, more than 1000 nM of HM71224 was required to inhibit 50 % of cellular growth in EGFR-overexpressed A431 cells (Additional file 1: Figure S2A) or phosphorylation of EGFR (Additional file 1: Figure S2B).Fig. 1

Bottom Line: 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.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.Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea.

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.

No MeSH data available.


Related in: MedlinePlus