BLZ945CSF-1R kinase inhibitor CAS# 953769-46-5 |
- GW2580
Catalog No.:BCC1096
CAS No.:870483-87-7
Quality Control & MSDS
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Chemical structure
3D structure
| 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. |
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| 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. |
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| 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. | ||
| 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.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: | |||||
BLZ945 Dilution Calculator
BLZ945 Molarity Calculator
| 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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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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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.
