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1mg |
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Gilteritinib-d8 is the octa-deuterated form of Gilteritinib (ASP-2215), which is a potent and ATP-competitive FLT3/AXL inhibitor with IC50s of 0.29 nM/0.73 nM, respectively. Gilteritinib (Xospata) has been approved for treating acute myeloid leukemia (AML). It inhibits FLT3 and AXL with IC50 values of 0.29 nM and 0.73 nM, respectively. Gilteritinib potently inhibits FLT3 with an IC50 that is about 800-fold higher than the concentration required to inhibit c-KIT (230 nM). Gilteritinib has the potential to treat leukemia such as AML with either or both FLT3-ITD and FLT3-D835 mutations. In vitro, among the 78 tyrosine kinases tested, Gilteritinib at 1 nM concentration inhibits FLT3, leukocyte tyrosine kinase (LTK), anaplastic lymphoma kinase (ALK), and AXL kinases by over 50% with an IC50 value of 0.29 nM for FLT3, and is approximately 800-fold more potent than for c-KIT. As of November 2018, Gilteritinib was approved by US FDA to treat patients who have relapsed or refractory acute myeloid leukemia (AML).
ln Vitro |
Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].
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References |
[1]. Russak EM, et al. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019;53(2):211-216.
[2]. ASP2215, a novel FLT3/AXL inhibitor: Preclinical evaluation in acute myeloid leukemia (AML). 2014 ASCO Annual Meeting. [3]. Mori M, et al. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017 Oct;35(5):556-565. |
Molecular Formula |
C29H44N8O3
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Molecular Weight |
552.711465835571
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CAS # |
2377109-74-3
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Related CAS # |
Gilteritinib;1254053-43-4
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Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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SMILES |
N(C1C=CC(N2CCC(N3C([H])([H])C([H])([H])N(C)C([H])([H])C3([H])[H])CC2)=C(OC)C=1)C1=NC(NC2CCOCC2)=C(CC)N=C1C(=O)N
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.8093 mL | 9.0463 mL | 18.0927 mL | |
5 mM | 0.3619 mL | 1.8093 mL | 3.6185 mL | |
10 mM | 0.1809 mL | 0.9046 mL | 1.8093 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.
In Vitro |
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In vitroactivity:In vitro, among the 78 tyrosine kinases tested, Gilteritinib at 1 nM concentration inhibits FLT3, leukocyte tyrosine kinase (LTK), anaplastic lymphoma kinase (ALK), and AXL kinases by over 50% with an IC50value of 0.29 nM for FLT3, and is about 800-fold more potent than for c-KIT.Gilteritinib inhibits eight of the 78 tested kinases by over 50% at concentrations of either 1 nM (FLT3, LTK, ALK, and AXL) or 5 nM (TRKA, ROS, RET, and MER). The IC50values are 0.29 nM for FLT3 and 0.73 nM for AXL. Gilteritinib inhibits FLT3 at an IC50that is approximately 800-fold more potent than the concentration required to inhibit c-KIT (230 nM). The antiproliferative activity of Gilteritinib is evaluated against MV4-11 and MOLM-13 cells, which endogenously express FLT3-ITD. After 5 days of treatment, Gilteritinib inhibits the growth of MV4-11 and MOLM-13 cells with mean IC50s of 0.92 nM (95% CI: 0.23-3.6 nM) and 2.9 nM (95% CI: 1.4-5.8 nM), respectively. Growth suppression of MV4-11 cells is accompanied by inhibition of FLT3 phosphorylation. Relative to vehicle control cells, phosphorylated FLT3 levels are 57%, 8%, and 1% after 2 h of treatment with 0.1 nM, 1 nM, and 10 nM Gilteritinib, respectively. In addition, doses as low as 0.1 nM or 1 nM result in the suppression of phosphorylated ERK, STAT5, and AKT, all of which are downstream targets of FLT3 activation. To investigate the effects of Gilteritinib on AXL inhibition, MV4-11 cells that expressed exogenous AXL are treated with Gilteritinib. At concentrations of 1 nM, 10 nM, and 100 nM for 4 h, Gilteritinib treatment decreases phosphorylated AXL levels by 38%, 29%, and 22%, respectively. Kinase Assay:Gilteritinib was tested in a panel of 78 tested kinases using ATP concentrations that are approximately equal to the Kmvalue for each kinase in a TK-ELISA or off-chip mobility shift assay. Initially, two concentrations of Gilteritinib (1 nM and 5 nM) are tested to assess each compound’s inhibitory effect on TK activity. Further studies are then conducted using a dose range of Gilteritinib to determine IC50values for kinases in which activity is inhibited by >50% with 1 nM Gilteritinib as well as for c-KIT. TK-ELISA and MSA assays are used to conduct IC50studies for FLT3, LTK, AXL, and c-KIT; the HTRF KinEASE-TK assay is performed to assess the IC50value of echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK). Cell Assay:MV4-11 cells treated with DMSO or increasing concentrations of gilteritinib are incubated for 2 hours. Immunoprecipitation and immunoblot for phosphorylated FLT3 and total FLT3 are performed. td> |
In Vivo |
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