1. Protein Tyrosine Kinase/RTK
  2. c-Fms

BLZ945 

Cat. No.: HY-12768 Purity: 98.57%
Data Sheet SDS Handling Instructions

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.

For research use only. We do not sell to patients.
BLZ945 Chemical Structure

BLZ945 Chemical Structure

CAS No. : 953769-46-5

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10 mM * 1 mL in DMSO $110 In-stock
5 mg $100 In-stock
10 mg $150 In-stock
50 mg $450 In-stock
100 mg $690 In-stock
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  • Biological Activity

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  • Technical Information

  • Purity & Documentation

  • References

Description

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 μM (c-Kit), 4.8 μM (PDGFRβ), 9.1 μM (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 ~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].

Clinical Trial
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References
Preparing Stock Solutions
Concentration Volume Mass 1 mg 5 mg 10 mg
1 mM 2.5095 mL 12.5477 mL 25.0954 mL
5 mM 0.5019 mL 2.5095 mL 5.0191 mL
10 mM 0.2510 mL 1.2548 mL 2.5095 mL
Please refer to the solubility information to select the appropriate solvent.
Cell Assay
[1]

BLZ945 is dissolved in DMSO and stored, and then diluted with appropriate medium before use[1].

Cell growth rate is determined using the MTT cell proliferation kit. Briefly, cells are plated in triplicate in 96-well plates: 1×103 cells per well for glioma cell lines, 5×103 cells per well for BMDM and CRL-2467, and 2.5×103 cells per well for HUVEC and HBMEC cell lines. For all experiments, media is changed every 48 h. Cells are grown in the presence or absence of 6.7-6,700 nM of BLZ945, or 8 μg/mL of CSF-1R neutralizing antibody. To test the sensitivity to PDGFR inhibition, PDGC lines are cultured in the presence of 10,000 nM imatinib or 10,000 nM PTK787 (diluted from 10 mM stock solutions in DMSO). HUVEC and HBMEC cells are supplemented with ECGF supplied by the manufacturer unless otherwise indicated. Reduction of the MTT substrate is detected by colorimetric analysis using a plate reader as per the manufacturer’s protocol. 10 μL of MTT labeling reagent is added to each well and then incubated for 4 h at 37°C, followed by the addition of 100 μL MTT solubilization reagent overnight. The mixture is gently resuspended and absorbance is measured at 595 nm and 750 nm on a spectraMax 340pc plate reader[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[2]

BLZ945 is prepared in 20% Captisol (Mice)[2].

Mice[2]
Tumors are measured using calipers and volumes calculated based on the formula: volume=(width)2×length/2. In MMTV-PyMT mouse studies, 56-63 d old female mice are randomized into groups based on tumor volumes and dosed with either 20% Captisol vehicle or 200 mg/kg BLZ945. Dosing is administered by oral gavage once daily and tumor volumes are measured twice weekly. 5A1 rat anti-mouse CSF1 neutralizing antibody or rat IgG control is dosed at 10 mg/kg by intraperitoneal injection every 5 d. To calculate pulmonary metastasis in MMTV-PyMT transgenic mice, formalin-fixed paraffin-embedded lungs are serially sectioned and stained with hematoxylin and eosin. Tumor regions are scored by tumor burden (total tumor area divided by total lung area), size (tumor diameter), and according to the total number of individual metastases counted in a single-blind fashion. These values are averaged across the entire depth of the lung to obtain the final value. For K14-HPV16 mouse studies, female mice are given slow release 17β-estradiol pellets every 2 mo to induce squamous carcinogenesis in the cervical and vaginal epithelium. Mice are randomized at 6 mo of age at the reported onset of cervical cancer and treated with BLZ945 for a 1 mo duration. To determine cervical tumor volume in K14-HPV16 transgenic mice, formalin-fixed paraffin-embedded cervix tissues and neoplasms are serially sectioned, scored for tumor area in a single-blind fashion, and the values multiplied by the tumor depth. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

398.48

Formula

C₂₀H₂₂N₄O₃S

CAS No.

953769-46-5

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 30 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 98.57%

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BLZ945
Cat. No.:
HY-12768
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