BLZ945

953769-46-5

C20H22N4O3S

DMSO : >= 30 mg/mL (75.29 mM)

Protein Tyrosine Kinase/RTK

BLZ945 is a brain-penetrant CSF-1R inhibitor. The biochemical IC₅₀ for CSF-1R is 1 nM, which is >3200-fold higher than its affinity for other kinases. IC50 & Target: IC50: 1 nM (CSF-1R), 3.2 uM (c-Kit), 4.8 uM (PDGFRbeta), 9.1 uM (Flt3)^[1] In Vitro: Treatment of bone marrow-derived macrophages (BMDMs) with BLZ945 inhibits CSF-1-dependent proliferation (EC₅₀=67 nM), and decreases CSF-1R phosphorylation, similar to CSF-1R antibody blockade. BLZ945 also reduces viability of CRL-2467 microglia, Ink4a/Arf^?/? BMDMs (PDG genetic background), and NOD/SCID BMDMs. Importantly, BLZ945 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, BLZ945 has no direct effects on glioma cells, and perturbs macrophage survival through CSF-1R inhibition^[1]. In Vivo: Mice are treated with BLZ945 or vehicle, and evaluated for symptom-free survival. Median survival in the vehicle-treated cohort is 5.7 weeks. In striking contrast, BLZ945 significantly improves long-term survival with 64.3% surviving to the 26-week trial endpoint. This endpoint is chosen because Ink4a/Arf^?/? mice develop spontaneous tumors, including lymphomas and sarcomas, beginning at ca.30 weeks. BLZ945 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, BLZ945-treated animals have significantly less-malignant tumors, and no detectable lesions in 55.6% of asymptomatic mice at the endpoint^[1]. Mice receiving BLZ945 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)^[2].