BLZ945

CSF-1R kinase inhibitor CAS# 953769-46-5

BLZ945

Catalog No. BCC5583----Order now to get a substantial discount!

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Chemical structure

BLZ945

3D structure

Chemical Properties of BLZ945

Cas No. 953769-46-5 SDF Download SDF
PubChem ID 46184986 Appearance Powder
Formula C20H22N4O3S M.Wt 398.48
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 125 mg/mL (313.69 mM; Need ultrasonic)
Chemical Name 4-[[2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-1,3-benzothiazol-6-yl]oxy]-N-methylpyridine-2-carboxamide
SMILES CNC(=O)C1=NC=CC(=C1)OC2=CC3=C(C=C2)N=C(S3)NC4CCCCC4O
Standard InChIKey ADZBMFGQQWPHMJ-RHSMWYFYSA-N
Standard InChI InChI=1S/C20H22N4O3S/c1-21-19(26)16-10-13(8-9-22-16)27-12-6-7-15-18(11-12)28-20(24-15)23-14-4-2-3-5-17(14)25/h6-11,14,17,25H,2-5H2,1H3,(H,21,26)(H,23,24)/t14-,17-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of BLZ945

DescriptionBLZ945 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.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].

References:
[1]. Pyonteck SM, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013 Oct;19(10):1264-72. [2]. Strachan DC, et al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. Oncoimmunology. 2013 Dec 1;2(12):e26968.

Protocol

Cell Assay [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].

Animal Administration [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.

References:
[1]. Pyonteck SM, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013 Oct;19(10):1264-72. [2]. Strachan DC, et al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. Oncoimmunology. 2013 Dec 1;2(12):e26968.

BLZ945 Dilution Calculator

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BLZ945 Molarity Calculator

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Preparing Stock Solutions of BLZ945

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.5095 mL 12.5477 mL 25.0954 mL 50.1907 mL 62.7384 mL
5 mM 0.5019 mL 2.5095 mL 5.0191 mL 10.0381 mL 12.5477 mL
10 mM 0.251 mL 1.2548 mL 2.5095 mL 5.0191 mL 6.2738 mL
50 mM 0.0502 mL 0.251 mL 0.5019 mL 1.0038 mL 1.2548 mL
100 mM 0.0251 mL 0.1255 mL 0.251 mL 0.5019 mL 0.6274 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on BLZ945

BLZ945, also named as 4-[2((1R,2R)-2-Hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine- 2-carboxylic acid methylamide , is a small molecule inhibitor of CSF-1R kinase with IC50 value of 1.2 nM. [2]
CSF-1R is the receptor for macrophage colony stimulating factor (M-CSF) which mediates the biological effects of this cytokine. The main biological effects of CSF-1R signaling are differentiation, proliferation, migration and survival of precursor macrophages and osteoclasts from the monocytic lineage [1].  
BLZ945 has the potential to treat an array of diseases associated with normal and deregulated function of precursor macrophages and osteoclasts from the monocytic lineage. [14C]BLZ945 metabolites were kinetically and structurally characterized from an in vitro across species comparison study using human hepatocytes and microsomes. Both compounds BLZ945 and M9 have significant anti-proliferative activity against the M-CSF dependent cell line MNFS-60 with EC50 of 71 and 140 mM, respectively. The biotransformation of BLZ945 in human liver micro-omes and recombinant cytochromes occurred predominantly via oxidative routes with also a secondary reductive pathway. [2]
BLZ945 decreased the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. BLZ945 prevented tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. [3]
References:
[1]. Stanley ER, Berg KL, Einstein DB et al. Biology and action of colony--stimulating factor-1. Mol Reprod Dev. 1997 Jan;46(1):4-10.
[2]. Krauser JA, Jin Y, Walles M et al. Phenotypic and metabolic investigation of a CSF-1R kinase receptor inhibitor (BLZ945) and its pharmacologically active metabolite. Xenobiotica. 2015 Feb;45(2):107-23.
[3]. Strachan DC, Ruffell B2, Oei Y et al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. Oncoimmunology. 2013 Dec 1;2(12):e26968.

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References on BLZ945

Phenotypic and metabolic investigation of a CSF-1R kinase receptor inhibitor (BLZ945) and its pharmacologically active metabolite.[Pubmed:25180976]

Xenobiotica. 2015 Feb;45(2):107-23.

1. 4-[2((1R,2R)-2-Hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxyl ic acid methylamide (BLZ945) is a small molecule inhibitor of CSF-1R kinase activity within osteoclasts designed to prevent skeletal related events in metastatic disease. Key metabolites were enzymatically and structurally characterized to understand the metabolic fate of BLZ945 and pharmacological implications. The relative intrinsic clearances for metabolites were derived from in vitro studies using human hepatocytes, microsomes and phenotyped with recombinant P450 enzymes. 2. Formation of a pharmacologically active metabolite (M9) was observed in human hepatocytes. The M9 metabolite is a structural isomer (diastereomer) of BLZ945 and is about 4-fold less potent. This isomer was enzymatically formed via P450 oxidation of the BLZ945 hydroxyl group, followed by aldo-keto reduction to the alcohol (M9). 3. Two reaction phenotyping approaches based on fractional clearances were applied to BLZ945 using hepatocytes and liver microsomes. The fraction metabolized (fm) or contribution ratio was determined for each metabolic reaction type (oxidation, glucuronidation or isomerization) as well as for each metabolite. The results quantitatively illustrate contribution ratios of the involved enzymes and pathways, e.g. the isomerization to metabolite M9 accounted for 24% intrinsic clearance in human hepatocytes. In summary, contribution ratios for the Phase I and Phase II pathways can be determined in hepatocytes.

Description

BLZ945 is a potent, selective and brain-penetrant CSF-1R (c-Fms) inhibitor with an IC50 of 1 nM, showing more than 1,000-fold selectivity against its closest receptor tyrosine kinase homologs.

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