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Purity: =98.30%
Sotuletinib (formerly BLZ945; BLZ-945) is a novel, potent, selective, orally bioactive, and brain-penetrant CSF-1R (colony stimulating factor 1 receptor) inhibitor with potential antitumor activity. It exhibits 1000-fold higher selectivity against its closest receptor tyrosine kinase homologs and inhibits CSF-1R with an IC50 of 1 nM. Glioma-bearing mice demonstrate high in vivo antitumor efficaciousness of BLZ945. Sotuletinib was designated as an orphan drug by the US FDA in August 2022 in order to treat patients suffering from Amyotrophic Lateral Sclerosis (ALS), a progressive neurological disorder that affects nerve cells in the brain and spinal cord and results in loss of motor control.
| Targets |
CSF-1R (IC50 = 1 nM); c-Kit (IC50 = 3.2 μM); PDGFRβ (IC50 = 4.8 μM); Flt3 (IC50 = 9.1 μM)
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| ln Vitro |
BLZ945 specifically reduces CSF-1R phosphorylation and inhibits CSF-1-dependent proliferation in bone marrow-derived macrophages (BMDMs) with an EC50 of 67nM. In order to promote tumorigenesis, BLZ945 inhibits the reciprocal effects that macrophages and glioma cells have on one another's survival, proliferation, and/or polarization.[1]
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| ln Vivo |
BLZ945 inhibits CSF-1R to stop tumor growth and dramatically increase survival in mice with gliomas. Additionally, proneural tumor spheres and cell lines derived from patients are inhibited in vivo from growing orthotopically by BLZ945.[1] In both the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis and the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis, BLZ945 (200 mg/kg, p.o.) inhibits the growth of malignant cells.[2]
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| Enzyme Assay |
BLZ945 is a potent, orally bioactive, and selective CSF-1R (colony stimulating factor 1 receptor) inhibitor with IC50 of 1 nM, it is more than 1000-fold selective against its closest receptor tyrosine kinase homologs.
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| Cell Assay |
The MTT cell proliferation kit is used to calculate the rate of cell growth. In a nutshell, 96-well plates are used to plate cells in triplicate: 1 ×103 cells for glioma cell lines, 5 ×103 cells for BMDM and CRL-2467, and 2.5 ×103 cells for HUVEC and HBMEC cell lines. Every 48 hours, the media used in all experiments is changed. The cells are cultured with or without 8 μg/mL of CSF-1R neutralizing antibody or 6.7–6,700 nM of sotuletinib. PDGC lines are cultivated in the presence of 10,000 nM PTK787 or 10,000 nM STI571 (diluted from 10 mM stock solutions in DMSO) in order to test the sensitivity to PDGFR inhibition. ECGF supplied by the manufacturer is added to HUVEC and HBMEC cells, unless specified otherwise. With a plate reader and colorimetric analysis, the manufacturer's protocol is followed to detect the reduction of the MTT substrate. Before adding 100 μL of MTT solubilization reagent and letting it sit overnight at 37°C, 10 μL of MTT labeling reagent is added to each well and allowed to incubate for 4 hours. Utilizing a SpectraMax 340pc plate reader, the mixture is gently resuspended and absorbance is measured at 595 and 750 nm[1].
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| Animal Protocol |
Mice: Volumes of tumors are measured with calipers using the following formula: volume=(width)2×length/2. 56–63 day old female mice are dosed with 200 mg/kg of sotuletinib or 20% Captisol vehicle in MMTV-PyMT mouse studies. The mice are randomized into groups according to the sizes of their tumors. Tumor volumes are measured twice a week, and the dosage is given orally via gavage once a day. Rat IgG control or 5A1 rat anti-mouse CSF1 neutralizing antibody is injected intraperitoneally every five days at a dose of 10 mg/kg. Formalin-fixed paraffin-embedded lungs in MMTV-PyMT transgenic mice are serially sectioned and stained with hematoxylin and eosin to determine pulmonary metastasis. Tumor regions are rated based on size (tumor diameter), tumor burden (total tumor area divided by total lung area), and the total number of individual metastases counted in a single-blind manner. To get the final value, these values are averaged over the whole lung depth.
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| References |
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| Molecular Formula |
C20H22N4O3S
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|---|---|
| Molecular Weight |
398.48
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| Exact Mass |
398.14
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| Elemental Analysis |
C, 60.28; H, 5.57; N, 14.06; O, 12.04; S, 8.05
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| CAS # |
953769-46-5
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| Related CAS # |
Sotuletinib hydrochloride;2222138-31-8;Sotuletinib dihydrochloride;2222138-40-9
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| Appearance |
Solid powder
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| SMILES |
CNC(=O)C1=NC=CC(=C1)OC2=CC3=C(C=C2)N=C(S3)N[C@@H]4CCCC[C@H]4O
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| InChi Key |
ADZBMFGQQWPHMJ-RHSMWYFYSA-N
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| InChi Code |
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
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| Chemical Name |
4-[[2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-1,3-benzothiazol-6-yl]oxy]-N-methylpyridine-2-carboxamide
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| Synonyms |
BLZ-945; Sotuletinib; BLZ 945; BLZ945
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Treatment with BLZ945 reduces macrophages, enhances T cell infiltration, and prevents tumor growth in the K14-HPV16 transgenic mouse model of cervical carcinoma. Oncoimmunology. 2013 Dec 1; 2(12): e26968. Sotuletinib (formerlyBLZ945; BLZ-945) is a novel, potent, selective, orally bioactive,and brain-penetrantCSF-1R (colony stimulating factor 1 receptor) inhibitor with potential antitumor activity. It inhibits CSF-1R with an IC50 of 1 nM, and shows 1000-fold higher selectivity against its closest receptor tyrosine kinase homologs.BLZ945 shows high in vivo antitumor efficacy in glioma-bearing mice. In Aug 2022, the USFDA granted orphan drug designation to sotuletinib to treat patients with Amyotrophic Lateral Sclerosis (ALS), which isa progressive nervous system disorder affecting nerve cells in the brain and spinal cord, leading to loss of muscle control. References:Nat Med.2013 Oct;19(10):1264-72;Oncoimmunology.2013 Dec 1;2(12):e26968. |
Treatment with BLZ945 decreases macrophage content in tumor and liver, but does not affect lung macrophages, circulating monocytes or tumor cell proliferation. Oncoimmunology. 2013 Dec 1; 2(12): e26968. |
Pharmacological blockade of CSF1R signaling increases infiltration of T cells and decreases tumor growth but does not affect pulmonary metastasis in PyMT mice. Oncoimmunology. 2013 Dec 1;2(12):e26968. |
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