Pexidartinib is a small-molecule receptor tyrosine kinase (RTK) inhibitor of KIT, CSF1R and FLT3 with IC50s of 20, 10, and 160 nM in vitro, respectively.
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].
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