BLZ945

Research use only, not for human use.

BLZ945 (BLZ-945) is a potent, selective, brain-penetrant CSF-1R inhibitor with biochemical IC50 of 1 nM.

BLZ945 (BLZ-945) is a potent, selective, brain-penetrant CSF-1R inhibitor with biochemical IC50 of 1 nM, displays >3,200-fold selectivity over other kinases (c-Kit, PDGFR-β, Flt3, Abl, etc.); inhibits CSF-1-dependent proliferation in bone marrow-derived macrophages (BMDMs) with EC50 of 67 nM, and decreases CSF-1R phosphorylation; blocks glioma progression and significantly improves survival, efficiently limits tumor progression combining with PD-1/PD-L1 blocking antibodies in neuroblastoma.Solid Tumors Phase 2 Clinical(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 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 ~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).

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, 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.

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).

BLZ-945

Tyrosine Kinase

CSF1R

CSF-1R

Cancer

Solid Tumors

953769-46-5

398.4787

C20H22N4O3S

>98% (HPLC)

DMSO: ≥ 30 mg/mL

O=C(NC)C1=NC=CC(OC2=CC3=C(N=C(N[C@@H]4CCCC[C@H]4O)S3)C=C2)=C1

2-Pyridinecarboxamide, 4-[[2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolyl]oxy]-N-methyl-

(-20℃)

With Ice Pack

≥ 2 years