GW2580 is a selective inhibitor of CSF-1R with IC50 value of 60nM for cFMS kinase (measured by kinase activity), 150- to 500-fold selective compared to the other kinase tested including BRAF, CDK4, cKIT, cSRC, EGFR, ERBB2, ERBB4, ERK2, FLT-3, GSK3, ITK, JAK2, JNK3, MK2, P38, PDGFR-β, PDHK4, PKA, PKCα, PKCβI, PKCζ, SYK, TIE2 and VEGFR2, as well as mouse LCK kinases. Complete inhibition of CSF-1-dependent growth of mouse myeloid M-NFS-60 cells can be observed at 0.7μM by GW2580. Treatment with GW2580 at 1μM inhibited CSF-1-, GMCSF- and LPS-induced human monocytes growth by 100%, 80% and 50%, respectively. This can be also confirmed in vivo as oral dosed mice with GW2580 at 40mg/kg before CSF-1-priming dose completely blocked the ability of MCSF to increase LPS-induced IL-6 production, but slightly increased LPS-induced IL-6 production before vehicle-priming dose. It showed that oral dose with GW2580 at 20 and 80mg/kg, BID, before thioglycolate injection for 4 days could inhibit thioglycolate-induced macrophage Influx into the peritoneal cavity in vivo. Oral administration of GW2580 at 20 and 80mg/kg, BID, at 1h before i.p. injection of M-NFS-60 cells, produced a dose-related decrease in the number of tumor cells in mice on 4 days later[1].
作用机制
GW2580 acts as a competitive inhibitor of ATP binding to the cFMS kinase.[1]
GW2580 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Mouse satellite glial cells (SGCs)
20 mg/mL
1, 3, 7 days
To evaluate the effect of PLGA and PLGAM microparticles on the proliferation of SGCs, results showed no significant effect on cell proliferation.
Acta Biomater. 2023 Apr 15;161:201-212.
Human adipose mesenchymal stem cells (ADMSCs)
20 mg/mL
1, 3, 7 days
To evaluate the effect of PLGA and PLGAM microparticles on the proliferation of ADMSCs, results showed no significant effect on cell proliferation.
Acta Biomater. 2023 Apr 15;161:201-212.
Mouse bone marrow mesenchymal stem cells (mBMSCs)
10 µM
24 and 72 hours
To study the effect of GW2580 on mBMSCs proliferation, adhesion, and osteogenic differentiation. Results showed that GW2580 did not affect mBMSCs function at the later stage of release and promoted osteogenesis.
Bioact Mater. 2022 May 2;19:474-485.
Mouse bone marrow-derived monocytes (BMMs)
10 µM
24 and 72 hours
To study the inhibitory effect of GW2580 on BMMs proliferation and osteoclast differentiation. Results showed that GW2580 significantly inhibited BMMs proliferation and osteoclast differentiation.
Bioact Mater. 2022 May 2;19:474-485.
Human peripheral blood mononuclear cells
470 nM or 4.7 µM
24 hours
To investigate the effect of GW2580 on M-CSF or IL-34-induced CD163 and CD16 expression, results showed GW2580 could inhibit the expression of these markers
J Neuroinflammation. 2015 Mar 25;12:58.
Rhesus macaque peripheral blood mononuclear cells
470 nM or 4.7 µM
24 hours
To investigate the effect of GW2580 on M-CSF or IL-34-induced CD163 and CD16 expression, results showed GW2580 could inhibit the expression of these markers
J Neuroinflammation. 2015 Mar 25;12:58.
Human osteoclasts
1 µM
3 days
Inhibited bone degradation and actin-ring formation
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83.
RAW264.7 cells
10 µM
4 hours
To study the inhibitory effect of GW2580 on CSF-1R and NF-κB signaling pathways. Results showed that released GW2580 effectively inhibited phosphorylation of CSF-1R and significantly attenuated phosphorylation of AKT and NF-κB signaling pathways.
Bioact Mater. 2022 May 2;19:474-485.
RAW 264.7 cells
10–1000 nM
48 hours
GW2580 reduced MCSF-stimulated production of TNF to basal levels.
J Clin Immunol. 2011 Dec;31(6):1010-20.
Primary microglia
5 µM
48 hours
To assess GW2580's effect on LPS-activated microglial viability. Results showed combined GW2580 and LPS treatment significantly reduced cell viability in a ROS-dependent manner.
Front Immunol. 2021 Nov 26;12:734349.
Primary microglia
5 µM
48 hours
To evaluate the effect of GW2580 on microglial proliferation. Results showed GW2580 dose-dependently inhibited CSF1-induced cell proliferation without affecting viability.
Front Immunol. 2021 Nov 26;12:734349.
Freshly isolated human monocytes
0.47 µM
5 days
Completely inhibited CSF-1-induced growth
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83.
Freshly isolated human monocytes
0.47 µM (IC50)
5 days
Completely inhibited CSF-1-induced growth
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83.
Mouse myeloid NS0 cells
13.5 µM (IC50)
No significant effect on CSF-1-independent cell growth
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83.
Mouse myeloid M-NFS-60 cells
0.33 µM (IC50)
Completely inhibited CSF-1-induced cell growth
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83.
Human islet cells
10 mg/ml
Assess toxicity of GW2580 on human islet cells
Nat Mater. 2019 Aug;18(8):892-904.
GW2580 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Chronic cerebral hypoperfusion model
Oral
0.1% (1000 ppm)
6 weeks
GW2580 treatment prevented the expansion of microglial numbers in chronic hypoperfused white matter, attenuated hypoperfusion-induced white matter pathology, and rescued spatial learning impairments and to a lesser extent cognitive flexibility.
Glia. 2024 Feb;72(2):375-395
Mice
Chronic DRA-induced asthma model
Intranasal administration
1 ng/mouse
Twice a week for 6 weeks
Intranasal delivery of CDPL-GW nanoprobe significantly ameliorated asthma pathologies including allergen-specific serum IgE production, allergic lung and airway inflammation and airway hyper-responsiveness (AHR) with minimal pulmonary adverse reaction.
Allergy. 2020 Feb;75(2):357-369
C57BL/6 mice
Diabetic model
Intraperitoneal and subcutaneous implantation
10 mg/ml
Up to 15 months
Evaluate long-term anti-fibrotic effects and glycemic control of GW2580 in diabetic models
Nat Mater. 2019 Aug;18(8):892-904.
C57BL/6 mice
Experimental autoimmune encephalomyelitis (EAE) model
Oral
100 mg/kg
Every 12 hours until the end of the experiment
GW2580 ameliorated the severity of EAE, reduced the proportion of macrophages in the CNS, and decreased circulating TNF levels.
J Clin Immunol. 2011 Dec;31(6):1010-20.
Mice
Nephritis model
Oral gavage
100 mg/kg
Once daily for 10 days
GW2580 treatment ameliorated proteinuria and renal dysfunction in the nephritis model, reduced glomerular macrophage infiltration, and decreased the expression of inflammatory cytokines.
J Autoimmun. 2015 Feb;57:42-52
CX3CR1+/eGFP transgenic mice
Spinal cord injury model
Oral
150 mg/kg/day
1 week
GW2580 treatment reduced microglia proliferation, improved motor function recovery, and promoted tissue protection.
Theranostics. 2021 Jul 31;11(18):8640-8659
Mice
Breast cancer model
Oral gavage
160 mg/kg
Daily, starting one day after tumor cell inoculation
GW2580 inhibited macrophage infiltration and function, reversing stress-enhanced metastasis
Cancer Res. 2010 Sep 15;70(18):7042-52
C57BL/6 mice
ID8 epithelial ovarian cancer model
Oral
160 mg/kg
Once daily for 2 weeks
GW2580 treatment reduced infiltration of M2 macrophages, dramatically decreased ascites volume, and normalized the peritoneal vasculature.
Cancer Res. 2015 Nov 15;75(22):4742-52
Athymic nude mice
Orthotopic U251 glioma model
Oral
160 mg/kg/day
Daily for two weeks
GW2580 significantly reduced tumor growth, decreased infiltration of GFP+ BMDCs in the tumor microenvironment, and reduced myeloid (Gr1+ CD11b+ and F4/80+) and angiogenic (CD202b+ and VEGFR2+) cell signatures.
Cancer Lett. 2015 Dec 28;369(2):416-26
Mice
C3H/HEN mice and CD-1 nude mice
Oral
20 and 80 mg/kg
Twice daily for 4 days
Inhibited CSF-1-dependent tumor cell growth and macrophage accumulation
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83.
Dark agouti (DA) female rats
Experimental allergic encephalomyelitis (EAE)
Oral gavage
40 mg/kg
Once daily for 11 days
GW2580 treatment delayed the onset of the disease, significantly reduced the clinical severity, and prevented the relapse phase
J Neuroinflammation. 2016 Nov 15;13(1):291
Dark Agouti rats
Experimental Autoimmune Encephalomyelitis (EAE)
Oral gavage
40 mg/kg
Daily from day -1 to day 11 after immunization
GW2580 treatment decreased EAE clinical severity and prevents the relapse phase, reduced microglial proliferation and T-cell infiltration, and preserved BBB integrity.
Cells. 2025 Mar 12;14(6):414
BALB/c mice
4T1 breast tumor model
Subcutaneous implantation
50 mg/kg
Single implantation, lasting for 10 days
To study the anti-tumor effect and immunoregulatory role of GW2580-loaded scaffolds in vivo. Results showed that GW2580-loaded scaffolds significantly reduced the proportion of M2-type macrophages in the tumor and inhibited tumor growth.
Bioact Mater. 2022 May 2;19:474-485.
Microcebus murinus
Spinal cord injury model
Oral
7.2 mg/day
2 weeks
GW2580 treatment reduced microglia proliferation, improved motor function recovery, and promoted tissue protection.
Theranostics. 2021 Jul 31;11(18):8640-8659
C57BL/6J mice
Healthy mice
Oral gavage
80 mg/kg/day
Once daily for 8 days
To evaluate GW2580's effects on microglial morphology and function in healthy mice. Results showed GW2580 altered microglial morphology without affecting cell numbers or circulating immune cell percentages. RNA-seq analysis revealed downregulation of ROS-related genes.
Front Immunol. 2021 Nov 26;12:734349.
Mice
Influenza A virus infection model
Oral gavage
80 mg/kg/day
Once daily for 15 days
Evaluate reversal effect of CSF1R antagonist on infection-induced oligodendrocyte transcriptional changes
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