Colony-Stimulating-Factor Receptor-1 (CSF-1R) is a tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. CSF-1R promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. CSF-1R also promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration. In response to ligand binding, CSF-1R activates several signaling pathways. Reports inferred that CSF-1R may be involved in cancer progression.
Edicotinib, also termed JNJ-40346527, is a selective colony-stimulating factor-1 (CSF-1) receptor inhibitor. In lung cancer H1299 cells, edicotinib concentration dependently suppressed the level of Tyr 723, and the effect was obvious at the concentration of 250 nM. Edicotinib also concentration dependently inhibited the colony formation ability of lung cancer Calu-1, A549, H1975 and H1299 cell lines [5].
In a subcutaneous C57BL6 mice model of lung carcinoma established by implantation of LLC cells, edicotinib was administered at dose 20 mg/kg 6 days per week p.o.. The results indicated that this dose and schedule of edicotinib in combination of CXCR2 antagonist SB225002 administered at dose 2mg/kg 6 days a week i.p. had significant anti-tumor activity. The same combination of these two drugs in a subcutaneous mice model of B16F10 melanoma was also efficient [6]. According to another report, in a H1299 lung cancer xenograft established on NOD/SCID mice subcutaneously，treatment of edicotinib at the dose of 20 mg/kg by daily oral gavage for 16 days, in combination of cisplatin at the i.p. dose of 4 mg/kg once a week for 2 weeks had significant anti-tumor activity [5].
Edicotinib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
N13 murine microglia cell line
0.1, 1, 10, 100, 1000 nM
30 minutes
To assess the inhibitory effect of JNJ-527 on CSF1R phosphorylation. Results showed that JNJ-527 dose-dependently inhibited CSF1R activation and downstream ERK1/2 phosphorylation, with IC50 values of 18.6 nM and 22.5 nM, respectively.
Brain. 2019 Oct 1;142(10):3243-3264
NCI-H1975
0.24 ± 0.07 micromol/L
24 hours
Evaluate the effect of JNJ-40346527 on clonogenicity of NCI-H1975 cells, showing significant reduction in colony formation at submicromolar doses.
Oncotarget. 2016 Aug 30;7(35):56408-56421
NCI-H1299
0.33 ± 0.09 micromol/L
24 hours
Evaluate the effect of JNJ-40346527 on clonogenicity of NCI-H1299 cells, showing significant reduction in colony formation at submicromolar doses.
Oncotarget. 2016 Aug 30;7(35):56408-56421
A549
0.41 ± 0.5 micromol/L
24 hours
Evaluate the effect of JNJ-40346527 on clonogenicity of A549 cells, showing significant reduction in colony formation at submicromolar doses.
Oncotarget. 2016 Aug 30;7(35):56408-56421
Edicotinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD/SCID mice
H1299 xenograft model
Oral gavage
20 mg/kg
Once daily for 16 days
Evaluate the effect of JNJ-40346527 on H1299 xenograft tumor growth, showing significant inhibition of tumor growth, with stronger effects when combined with cisplatin.
Oncotarget. 2016 Aug 30;7(35):56408-56421
Mice
ME7 mouse model
Oral
30 mg/kg
Once daily for 4 weeks
To evaluate the effect of JNJ527 on TSPO signal in the ME7 mouse model, results showed that JNJ527 significantly reduced TSPO expression in Iba1+ microglia and neurons.
J Neuroinflammation. 2023 Apr 9;20(1):92
Mice
Melanoma, lung carcinoma, lymphoma, colon carcinoma, and breast carcinoma models
Oral
20 mg/kg
Once daily for 4-5 weeks
To evaluate the effect of CSF1R inhibitor on tumor growth, results showed that the inhibitor significantly reduced the proportion of TAM but increased the infiltration of PMN-MDSC
Cancer Cell. 2017 Nov 13;32(5):654-668. e5
Mice
ME7 prion model and P301S mouse tauopathy model
Oral gavage
3, 10, 30, 100 mg/kg
Once daily for five consecutive days or 4-8 weeks
To evaluate the in vivo effects of JNJ-527 in the ME7 prion model and P301S mouse tauopathy model. Results demonstrated that JNJ-527 significantly inhibited microglial proliferation, reduced inflammatory responses, improved behavioral deficits, and attenuated tau pathology and neurodegeneration.
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