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CAS No. : 953769-46-5
MCE 国际站:Sotuletinib
产品活性:Sotuletinib (BLZ945) 是一种有效,选择性和脑渗透性的 CSF-1R (c-Fms) 抑制剂,IC50 为 1 nM,选择性是其他受体酪氨酸激酶同系物的 1000 倍。
研究领域:Protein Tyrosine Kinase/RTK
作用靶点:c-Fms
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.
In Vivo: Mice are treated with Sotuletinib or vehicle, and evaluated for symptom-free survival. Median survival in the vehicle-treated cohort is 5.7 weeks. In striking contrast, Sotuletinib significantly improves long-term survival. This endpoint is chosen because Ink4a/Arf?/? mice develop spontaneous tumors, including lymphomas and sarcomas, beginning at ~30 weeks. Sotuletinib is well-tolerated over long-term treatment, with no visible side-effects, consistent with histopathological studies. Histological grading revealed high-grade, invasive gliomas in all vehicle-treated mice. By contrast, Sotuletinib-treated animals have significantly less-malignant tumors, and no detectable lesions in 55.6% of asymptomatic mice at the endpoint. Mice receiving Sotuletinib shows reduced CSF1R staining in both cervical tumors and the associated stroma, with a significant decrease in CSF1R+ stromal macrophages relative to vehicle-treated mice (P<0.05).
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