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Purity: ≥98%
Tandutinib (formerly also known as MLN-518, CT-53518, D06005, NSC726292), a piperazinyl quinazoline, is a novel, potent and selective FLT3 inhibitor/antagonist with potential antitumor activity. Its IC50 value for FLT3 inhibition is 0.22 μM. Tandutinib also inhibits c-Kit and PDGFR. It also inhibits FLT3 with a potency that is 15–20 times higher than that of CSF-1R and a selectivity that is >100 times higher than that of FGFR, EGFR, and KDR. By preventing the autophosphorylation of c-KIT, PDGF (platelet-derived growth factor) receptor tyrosine kinases, and FLT3 (FMS-Like Tyrosine kinase-3), tantutinib may have anticancer effects by preventing cell division and triggering apoptosis.
Targets |
c-Kit (IC50 = 0.17 μM); PDGFRβ (IC50 = 0.20 μM); FLT3 (IC50 = 0.22 μM); CSF-1R (IC50 = 3.43 μM)
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ln Vitro |
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ln Vivo |
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Enzyme Assay |
PDGFR family kinase autophosphorylation assays are cell-based enzyme-linked immunosorbent (ELISA) assays that use CHO cells expressing PDGFRβ wild-type, PDGFRβ/c-Kit chimeric protein, and PDGFRβ/Flt3, which contain the cytoplasmic domain of Flt-3 and c-Kit as well as the extracellular and transmembrane domains of PDGFRβ. Standard tissue culture conditions are used to grow cells to confluency in 96-well microtiter plates. After that, the cells are starved of serum for 16 hours. In summary, quiescent cells are cultured for 30 minutes at 37 °C with escalating concentrations of tantutinib, and then 8 nM PDGF-BB is added and left for 10 minutes. Lysate is obtained by centrifuging the cell lysate at 15,000g for 5 minutes after it has been lysed in 100 mM Tris, pH 7.5, 750 mM NaCl, 0.5% Triton X-100, 10 mM sodium pyrophosphate, 50 mM NaF, 10 μg/mL aprotinin, 10 μg/mL leupeptin, 1 mM phenylmethylsulfonyl fluoride, and 1 mM sodium vanadate. The lysates that have been clarified are then moved into a second microtiter plate, where the wells have been coated with 500 ng/well of 1B5B11 anti-PDGFRβ mAb and allowed to sit at room temperature for two hours. Plates are incubated at 37 °C for 60 minutes after being washed three times with binding buffer (0.3% gelatin, 25 mM HEPES, pH 7.5, 100 mM NaCl, 0.01% Tween 20). Following this, 250 ng/mL of rabbit polyclonal anti-phosphotyrosine antibody is added. Then, each well is incubated with 1 μg/mL of horseradish peroxidase-conjugated anti-rabbit antibody for 60 minutes at 37 °C after being cleaned three times with binding buffer. Before adding 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), the wells are cleaned, and the rate of substrate formation is kept track of at 650 nm.
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Cell Assay |
Tandutinib is exposed to cells at escalating concentrations (0.004-30 μM). Viable cells are counted after 3–7 days of cell growth in tissue culture, as assessed by Trypan blue dye exclusion. Cells are taken out, cleaned, and resuspended in 100 uL of binding buffer that has 140 mM NaCl, 2.5 mM CaCl2, and 10 mM HEPES (pH 7.4) in it every day. The cell suspension is mixed with 100 ng of annexin V-FITC and 250 ng of propidium iodide, and then it is incubated for 15 minutes at room temperature. Using a FACSort flow cytometer with an excitation wavelength of 488 nm, flow cytometry is carried out right after staining. The fluorescence of DNA propidium iodide staining and annexin V-FITC staining is measured at 585 nm and 515 nm, respectively.
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Animal Protocol |
Female athymic nude (nu/nu) mice injected with Ba/F3 cells expressing W51 FLT3-ITD mutant
40-120 mg/kg/day Orally by gavage |
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References | ||
Additional Infomation |
Tandutinib is an N-arylpiperazine that is piperazine in which the hydrogen attached to the nitrogen at position 1 is replaced by a 6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazolin-4-yl group, while the hydrogen attached to the nitrogen at position 4 is replaced by a (p-isopropoxyphenyl)aminocarbonyl group. Tandutinib is an inhibitor of tyrosine kinases FLT3, PDGFR and KIT. It has a role as an antineoplastic agent and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It is a N-carbamoylpiperazine, a N-arylpiperazine, a member of quinazolines, a member of piperidines, an aromatic ether, a tertiary amino compound and a member of phenylureas.
MLN518 is a novel, oral, small molecule designed to inhibit type III receptor tyrosine kinases, including FLT3, (platelet-derived growth-factor receptor) PDGFR and c-KIT. Tyrosine kinases are enzymes involved in several cellular processes and are known to be activated in cancer cells to drive tumor growth. AML patients with FLT3 mutations experience earlier disease relapse and shorter survival rates compared to patients without these mutations. Approximately 25 to 30 percent of all adult AML patients have a mutation of the FLT3 gene. The use of MLN518 to treat AML has been granted fast-track status by the U.S. Food and Drug Administration. Phase I/II trials are underway. Tandutinib is a piperazinyl quinazoline receptor tyrosine kinase inhibitor with antineoplastic activity. Tandutinib inhibits the autophosphorylation of FLT3 (FMS-Like Tyrosine kinase-3), c-KIT and PDGF (platelet-derived growth factor) receptor tyrosine kinases, thereby inhibiting cellular proliferation and inducing apoptosis. Drug Indication Investigated for use/treatment in leukemia (myeloid). Mechanism of Action MLN518 inhibits tyrosine kinases; Specifically, it is selective for FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR). Pharmacodynamics MLN518 is a novel quinazoline-based small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with that has been shown to have great efficacy in murine models of FLT3 ITD-positive leukemia. Experiments with mice demonstrate that at effective concentrations, MLN518 has mild toxicity toward normal hematopoiesis for FLT3 ITD-positive leukemia. MLN518 has also been shown to preferentially inhibit the growth of blast colonies from FLT3 ITD-positive as compared to ITD-negative patients with AML, without significantly affecting colony formation by normal human progenitor cells. |
Molecular Formula |
C31H42N6O4
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Molecular Weight |
562.7
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Exact Mass |
562.326
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Elemental Analysis |
C, 66.17; H, 7.52; N, 14.94; O, 11.37
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CAS # |
387867-13-2
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Related CAS # |
Tandutinib hydrochloride;2438900-70-8
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PubChem CID |
3038522
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Appearance |
White to light yellow solid powder
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Density |
1.2±0.1 g/cm3
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Boiling Point |
769.5±60.0 °C at 760 mmHg
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Melting Point |
177-178°C
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Flash Point |
419.2±32.9 °C
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Vapour Pressure |
0.0±2.6 mmHg at 25°C
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Index of Refraction |
1.611
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LogP |
3.48
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Hydrogen Bond Donor Count |
1
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Hydrogen Bond Acceptor Count |
8
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Rotatable Bond Count |
10
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Heavy Atom Count |
41
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Complexity |
783
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Defined Atom Stereocenter Count |
0
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SMILES |
O(C1=C(C([H])=C2C(=C1[H])N=C([H])N=C2N1C([H])([H])C([H])([H])N(C(N([H])C2C([H])=C([H])C(=C([H])C=2[H])OC([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C1([H])[H])OC([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H]
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InChi Key |
UXXQOJXBIDBUAC-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C31H42N6O4/c1-23(2)41-25-10-8-24(9-11-25)34-31(38)37-17-15-36(16-18-37)30-26-20-28(39-3)29(21-27(26)32-22-33-30)40-19-7-14-35-12-5-4-6-13-35/h8-11,20-23H,4-7,12-19H2,1-3H3,(H,34,38)
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Chemical Name |
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide
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Synonyms |
MLN 518; CT 53518; D06005; NSC726292; MLN-518; MLN0518; MLN 518; MLN518; NSC 726292; CT53518; NSC-726292; CT-53518; D-06005; D 06005; Tandutinib
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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) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.44 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.44 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 0.5% methylcellulose: 30mg/mL |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.7771 mL | 8.8857 mL | 17.7715 mL | |
5 mM | 0.3554 mL | 1.7771 mL | 3.5543 mL | |
10 mM | 0.1777 mL | 0.8886 mL | 1.7771 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.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT00390468 | Completed | Drug: Tandutinib | Metastatic Cancer Pain |
National Cancer Institute (NCI) |
October 2006 | Phase 2 |
NCT00667394 | Completed | Biological: Bevacizumab Drug: MLN-518 (Tandutinib) |
Glioblastoma Gliosarcoma |
National Cancer Institute (NCI) |
April 2008 | Phase 2 |
NCT00408902 | Completed | Other: laboratory biomarker analysis Drug: tandutinib |
Recurrent Renal Cell Cancer Stage IV Renal Cell Cancer |
National Cancer Institute (NCI) |
November 2006 | Phase 2 |
NCT00379080 | Completed | Drug: tandutinib Other: Tissue samples |
Adult Brain Tumor Adult Glioblastoma |
National Cancer Institute (NCI) |
January 2007 | Phase 1 Phase 2 |
NCT00274248 | Completed | Drug: MLN518 | Acute Myelogenous Leukemia | Millennium Pharmaceuticals, Inc. | March 2005 | Phase 1 |