Sotuletinib

Sotuletinib (BLZ945) is a potent, selective, orally active and brain-penetrant CSF-1R (c-Fms) inhibitor with an IC₅₀ of 1 nM, showing more than 1,000-fold selectivity against its closest receptor tyrosine kinase homologs. Sotuletinib can be used for microglia depletion, and for tumor and CNS-related disease research^[1][2][3][4]. IC50 & Target:IC50: 1 nM (CSF-1R), 3.2 μM (c-Kit), 4.8 μM (PDGFRβ), 9.1 μM (Flt3)^[1] In Vitro: Treatment of bone marrow-derived macrophages (BMDMs) with Sotuletinib inhibits CSF-1-dependent proliferation (EC₅₀=67 nM), and decreases CSF-1R phosphorylation, similar to CSF-1R antibody blockade. Sotuletinib also reduces viability of CRL-2467 microglia, Ink4a/Arf ^/ BMDMs (PDG genetic background), and NOD/SCID BMDMs. Importantly, Sotuletinib treatment in culture does not affect proliferation of any PDG-derived tumor cell lines (all Csf-1r-negative), or U-87 MG human glioma cells, and PDG cell tumor sphere formation is unaffected. Thus, Sotuletinib has no direct effects on glioma cells, and perturbs macrophage survival through CSF-1R inhibition^[1]. In Vivo: Sotuletinib (2,000 ppm in diet, 21 days) depletes more than 90% of microglia in C57BL6/J mice^[3].
Sotuletinib hydrochloride (200 mg/kg, p.o., 7 days) depletes more than 90% microglia in C57BL6/J mice, and subsequntenly used for microglia replacement^[4].
Sotuletinib (60-169 mg/kg, p.o., 5 days) dose- and time-dependently depletes microglia in C57BL6/J mice, and newly generated microglia after BLZ945 removal reached normal levels 3 days after last dose^[5].