BLZ945 _c-Fms 抑制剂 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEBLZ945Cat. No.: HY-12768CAS No.: 953769-46-5分式: CHNOS分量: 398.48作靶点: c-Fms作通路: Protein Tyrosine Kinase/RTK储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 30 mg/mL (75.29 mM)* means soluble,

2、but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.5095 mL 12.5477 mL 25.0954 mL5 mM 0.5019 mL 2.5095 mL 5.0191 mL10 mM 0.2510 mL 1.2548 mL 2.5095 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结果的可靠性，体内实验的作液，建议您现现配，当天使；澄清

3、的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.08 mg/mL (5.22 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.08 mg/mL (5.22 mM); Clear solution3. 请依序添加每种溶剂： 10% DMSO 90% corn oil1/3 Master of Small

4、 Molecules 您边的抑制剂师www.MedChemESolubility: 2.08 mg/mL (5.22 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 BLZ945种有效，选择性和脑渗透性的 CSF-1R 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。IC50 & Target IC50: 1 nM (CSF-1R), 3.2 M (c-Kit), 4.8 M (PDGFR), 9.1 M (Flt3) 1体外研究 Treatment of bone marrow-derived macrophages (BMDMs

5、) with BLZ945 inhibits CSF-1-dependentproliferation (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), andNOD/SCID BMDMs. Importantly, BLZ945 treatment in culture does

6、 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 sphereformation is unaffected. Thus, BLZ945 has no direct effects on glioma cells, and perturbs macrophagesurvival through CSF-1R inhibition 1.体内研究 Mice are treated

7、with BLZ945 or vehicle, and evaluated for symptom-free survival. Median survival in thevehicle-treated cohort is 5.7 weeks. In striking contrast, BLZ945 significantly improves long-term survival with64.3% surviving to the 26-week trial endpoint. This endpoint is chosen because Ink4a/Arf/ mice develo

8、pspontaneous tumors, including lymphomas and sarcomas, beginning at 30 weeks. BLZ945 is well-toleratedover long-term treatment, with no visible side-effects, consistent with histopathological studies. Histologicalgrading revealed high-grade, invasive gliomas in all vehicle-treated mice. By contrast,

9、 BLZ945-treatedanimals have significantly less-malignant tumors, and no detectable lesions in 55.6% of asymptomatic miceat the endpoint 1. Mice receiving BLZ945 shows reduced CSF1R staining in both cervical tumors and theassociated stroma, with a significant decrease in CSF1R+ stromal macrophages re

10、lative to vehicle-treatedmice (P 2.PROTOCOLCell Assay 1 Cell growth rate is determined using the MTT cell proliferation kit. Briefly, cells are plated in triplicate in 96-well plates: 1103 cells per well for glioma cell lines, 5103 cells per well for BMDM and CRL-2467, and2.5103 cells per well for H

11、UVEC 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 g/mL of CSF-1R neutralizingantibody. To test the sensitivity to PDGFR inhibition, PDGC lines are cultured in the presence of 10,000 nMimatinib or 10,

12、000 nM PTK787 (diluted from 10 mM stock solutions in DMSO). HUVEC and HBMEC cells aresupplemented with ECGF supplied by the manufacturer unless otherwise indicated. Reduction of the MTTsubstrate is detected by colorimetric analysis using a plate reader as per the manufacturers protocol. 10 Lof MTT l

13、abeling reagent is added to each well and then incubated for 4 h at 37C, followed by the addition of100 L MTT solubilization reagent overnight. The mixture is gently resuspended and absorbance ismeasured at 595 nm and 750 nm on a spectraMax 340pc plate reader 1.MCE has not independently confirmed th

14、e accuracy of these methods. They are for reference only.2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEAnimal Mice 2Administration 2 Tumors are measured using calipers and volumes calculated based on the formula:volume=(width)2length/2. In MMTV-PyMT mouse studies, 56-63 d old female mice are rand

15、omized intogroups based on tumor volumes and dosed with either 20% Captisol vehicle or 200 mg/kg BLZ945. Dosing isadministered by oral gavage once daily and tumor volumes are measured twice weekly. 5A1 rat anti-mouseCSF1 neutralizing antibody or rat IgG control is dosed at 10 mg/kg by intraperitonea

16、l injection every 5 d. Tocalculate pulmonary metastasis in MMTV-PyMT transgenic mice, formalin-fixed paraffin-embedded lungs areserially sectioned and stained with hematoxylin and eosin. Tumor regions are scored by tumor burden (totaltumor area divided by total lung area), size (tumor diameter), and

17、 according to the total number of individualmetastases counted in a single-blind fashion. These values are averaged across the entire depth of the lungto obtain the final value. For K14-HPV16 mouse studies, female mice are given slow release 17-estradiolpellets every 2 mo to induce squamous carcinog

18、enesis in the cervical and vaginal epithelium. Mice arerandomized at 6 mo of age at the reported onset of cervical cancer and treated with BLZ945 for a 1 moduration. To determine cervical tumor volume in K14-HPV16 transgenic mice, formalin-fixed paraffin-embedded cervix tissues and neoplasms are ser

19、ially sectioned, scored for tumor area in a single-blindfashion, and the values multiplied by the tumor depth.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 Clin Cancer Res. 2018 Mar 1;24(5):1176-1189. Nat Biomed Eng. 2018;2:578-588.See more customer vali