The inhibition of CSF-1R, which can deplete macrophages and reduce tumor volume, is an effective strategy to treat for glioblastoma multiforme because of the crucial function of CSF-1R through the paracrine CSF-1–EGF signaling loop in glioma microenvironment forming by the tumor-associated macrophages and microglia (TAMs). Pexidartinib is a muti-target inhibitor with IC50 values of 10nM, 20nM and 160nM for c-kit and CSF-1R (measured by in vitro kinase assays), 10- to 100-fold selectivity against other 226 different kinases tested. Inhibition of CSF-1R by Pexidartinib could alter tumor immune microenvironment in vivo thus significantly decreasing primary tumor progression and enhancing the common cytotoxic drugs, like paclitaxel, in breast cancer. Instead of altering TAMs maturation of differentiation, treatment with Pexidartinib significantly inhibited both steady-state and paclitaxel-induced infiltration by TAMs in late-stage MMTV-PyMT mice. Combined paclitaxel therapy with CSF1-signaling blockade by Pexidartinib can foster an antitumor immune response by increased T lymphocytes (CD4+ and CD8+ T cells) with high expression of cytotoxic effector molecules, such as IFN-, granzyme A, granzyme B, perforin-1, the type 1 DC effector molecules, IL12p35 and IFN-α, in mammary tumors, which may due to the macrophage depletion. Thus this facilitate the enhanced cytotoxic response and block of metastasis, both of which were CD8+ T-cell-dependent. Oral treatment with 40mg/kg Pexidartinib for 5 days, followed with 10 mg/kg paclitaxel, i.v., for 4 cycles, caused reduce of primary tumor burden in MMTV-PyMT mice[1].
Blocking the CSF1 receptor reduced CD163+M2 macrophage differentiation induced by EBV-infected tumor supernatant
J Immunother Cancer. 2024 Jun 17;12(6):e008375.
MOLM-14
51 nM
48 h
To evaluate the inhibitory effect of Pexidartinib on MOLM-14 cells, results showed that cell viability decreased with increasing drug concentration.
Cancer Cell Int. 2021 Apr 8;21(1):198.
MV4-11
37 nM
48 h
To evaluate the inhibitory effect of Pexidartinib on MV4-11 cells, results showed that cell viability decreased with increasing drug concentration.
Cancer Cell Int. 2021 Apr 8;21(1):198.
RAW264.7 macrophages
5 μg/mL
24 h
To evaluate the effect of Pexidartinib on macrophage polarization, the results showed that Pexidartinib could induce macrophage polarization to the M1 phenotype.
Nat Commun. 2022 Apr 25;13(1):2216.
HUVECs
30 nM
48 h
To evaluate the effect of Pexidartinib on HUVECs cell viability, the results showed that Pexidartinib significantly reduced the cell viability of HUVECs.
Cell Signal. 2022 Dec;100:110458.
MV4;11 cells
18 nM
To evaluate the inhibitory effect of PLX3397 on FLT3-ITD signaling
Cancer Discov. 2015 Jun;5(6):668-79.
RS4;11 cells
1.8 μM
To evaluate the inhibitory effect of PLX3397 on native FLT3 signaling
Cancer Discov. 2015 Jun;5(6):668-79.
Pexidartinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NCG mice
C666-1-A11-LMP2A subcutaneous xenograft model
Intraperitoneal injection
20 mg/kg
Twice a week, starting from the time of immune cell injection
MMP9 inhibitors restored TCR-T cell function suppressed by M2 macrophages, inhibiting the growth of EBV-infected tumors
J Immunother Cancer. 2024 Jun 17;12(6):e008375.
Mice
4T1 tumor model
Intratumoral injection
4 mg/mL
Injections on day 1, 3, and 5, lasting for 15 days
To evaluate the role of Pexidartinib in tumor immunotherapy, the results showed that Pexidartinib could significantly inhibit tumor growth and induce macrophage polarization to the M1 phenotype.
Nat Commun. 2022 Apr 25;13(1):2216.
Mice
Acute ventilator-induced lung injury model
Oral
600 mg/kg
Daily, for two weeks
To study the effect of Pexidartinib in depleting microglia by inhibiting CSF1R receptor in a mouse model and evaluate its impact on neuronal injury and delirium-like behaviors. Results showed that Pexidartinib significantly reduced microglia numbers and exacerbated neuronal injury and delirium-like behaviors.
J Neuroinflammation. 2024 Oct 21;21(1):270
Mice
P21 wildtype C57Bl/6 mice
Oral
290 mg/kg
7 days continuously
Eliminate microglia
Nature. 2017 Jan 26;541(7638):481-487
Mice
FVB/N mice
Oral gavage
45 mg/kg
Once daily for 2 weeks
To deplete macrophages by inhibiting CSF1R, results showed a significant reduction in macrophage counts in the mammary gland and increased levels of hyaluronan and collagen in the adipose stroma.
Elife. 2020 Jun 1;9:e57438
Mice
Acute ventilator-induced lung injury model
Oral
600 mg/kg
Daily for two weeks
To evaluate the effect of microglia depletion on VILI-induced neuronal injury and delirium-like behaviors. Results showed that PEXI-treated mice exhibited more severe neuronal injury and delirium-like behaviors after VILI.
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