Tandutinib (MLN518)

Catalog No.S1043 Synonyms: CT 53518, NSC726292, MLN518

Tandutinib (MLN518) Chemical Structure

Molecular Weight(MW): 562.7

Tandutinib (MLN518, CT53518) is a potent FLT3 antagonist with IC50 of 0.22 μM, also inhibits PDGFR and c-Kit, 15 to 20-fold higher potency for FLT3 versus CSF-1R and >100-fold selectivity for the same target versus FGFR, EGFR and KDR. Phase 2.

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2 Customer Reviews

  • A representative experiment for tandutinib is shown. A: The control group after 0 h. B: The control group after 24 h. C: Treatment with 0.125 ug/ml tandutinib. D: Treatment with 0.25 ug/ml tandutinib. E: Treatment with 0.5 ug/ml tandutinib. F: + Treatment with 1 ug/ml tandutinib. G: Treatment with 2 ug/ml tandutinib. H: Treatment with 5 ug/ml tandutinib. I: Treatment with 10 ug/ml tandutinib. (B) + (C) *, P < 0.05, compared with the respective uninhibited cells. The bars represent the mean ?SD.

    Br J Cancer 2012 107, 1702-13. Tandutinib (MLN518) purchased from Selleck.

    Eur J Pharm Sci 2013 49(3), 441-50. Tandutinib (MLN518) purchased from Selleck.

Purity & Quality Control

Choose Selective FLT3 Inhibitors

Biological Activity

Description Tandutinib (MLN518, CT53518) is a potent FLT3 antagonist with IC50 of 0.22 μM, also inhibits PDGFR and c-Kit, 15 to 20-fold higher potency for FLT3 versus CSF-1R and >100-fold selectivity for the same target versus FGFR, EGFR and KDR. Phase 2.
Targets
c-Kit [1] PDGFRβ [1] FLT3 [1]
()
CSF-1R [1]
0.17 μM 0.20 μM 0.22 μM 3.43 μM
In vitro

Tandutinib has little activity against EGFR, FGFR, KDR, InsR, Src, Abl, PKC, PKA and MAPKs. Tandutinib inhibits IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC50 of 10-100 nM. Tandutinib also inhibits the proliferation of human leukemia Ba/F3 cells containing FLT3-ITD mutations with IC50 values of 10-30 nM, and the FLT3-ITD-positive Molm-13 and Molm-14 cells with an IC50 of 10 nM. In FLT3-ITD-positive Molm-14 cells but not the FLT3-ITD-negative THP-1 cells, Tandutinib treatment leads to significant apoptosis by 51% and 78% at 24 and 96 hours, respectively, due to specific FLT3 inhibition. [1] Tandutinib preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, without affecting colony formation by normal human progenitor cells. [2]

In vivo Oral administration of Tandutinib at 60 mg/kg bid significantly increases the survival in mice bearing Ba/F3 cells expressing W51 FLT3-ITD mutant, and gives a significant reduction in mortality in a mouse bone marrow transplantation model. [1] Tandutinib treatment at 180 mg/kg twice daily has mild toxicity toward normal hematopoiesis, however, it is a dose at which Tandutinib is effective in treating FLT3 ITD-positive leukemia in mice. [2]

Protocol

Kinase Assay:[1]
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Cell based receptor autophosphorylation assays:

Autophosphorylation of PDGFR family kinase assays are cell-based enzyme-linked immunosorbent (ELISA) assays using CHO cells expressing wild-type PDGFRβ, chimeric protein PDGFRβ/c-Kit, and PDGFRβ/Flt3 which contain the extracellular and transmembrane domains of PDGFRβ and the cytoplasmic domain of c-Kit, and Flt-3. Cells are grown to confluency in 96-well microtiter plates under standard tissue culture conditions, followed by serum starvation for 16 hours. Briefly, quiescent cells are incubated at 37 °C with increasing concentrations of Tandutinib for 30 minutes followed by the addition of 8 nM PDGF-BB for 10 minutes. Cells are 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, 1 mM sodium vanadate, and the lysate is cleared by centrifugation at 15,000g for 5 minutes. Clarified lysates are transferred into a second microtiter plate in which the wells are previously coated with 500 ng/well of 1B5B11 anti-PDGFRβ mAb and then incubated for 2 hours at room temperature. After washing three times with binding buffer (0.3% gelatin, 25 mM HEPES, pH 7.5, 100 mM NaCl, 0.01% Tween 20), 250 ng/mL of rabbit polyclonal anti-phosphotyrosine antibody is added and plates are incubated at 37 °C for 60 minutes. Subsequently, each well is washed three times with binding buffer and incubated with 1 μg/mL of horseradish peroxidase-conjugated anti-rabbit antibody at 37 °C for 60 minutes. Wells are washed prior to adding 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), and the rate of substrate formation is monitored at 650 nm.
Cell Research:[1]
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  • Cell lines: Ba/F3, Molm-13, Molm-14, HL60, AML193, KG-1, KG-1a, THP-1, and RS4;11
  • Concentrations: Dissolved in DMSO, final concentrations ~30 μM
  • Incubation Time: ~7 days
  • Method: Cells are exposed to increasing concentrations of Tandutinib (0.004-30 μM). Cells are grown for 3-7 days in tissue culture, and viable cells, determined by Trypan blue dye exclusion, are counted. At daily intervals, cells are harvested, washed, and resuspended in 100 uL binding buffer containing 10 mM HEPES (pH 7.4), 140 mM NaCl, and 2.5 mM CaCl2. Annexin V-FITC (100 ng) and propidium iodide (250 ng) are added to the cell suspension followed by incubation at room temperature for 15 minutes. Flow cytometry is performed immediately after staining on a FACSort flow cytometer with excitation at 488 nm. Fluorescence of annexin V-FITC and DNA propidium iodide staining are measured at 515 nm and 585 nm, respectively.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Female athymic nude (nu/nu) mice injected with Ba/F3 cells expressing W51 FLT3-ITD mutant
  • Formulation: Suspended in a 0.5% methylcellulose (MC) in water solution
  • Dosages: 40-120 mg/kg/day
  • Administration: Orally by gavage
    (Only for Reference)

Solubility (25°C)

In vitro Ethanol 6 mg/mL (10.66 mM)
DMSO 5 mg/mL (8.88 mM)
Water Insoluble
In vivo Add solvents individually and in order:
0.5% methylcellulose
30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 562.7
Formula

C31H42N6O4

CAS No. 387867-13-2
Storage powder
Synonyms CT 53518, NSC726292, MLN518

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00904852 Withdrawn Glioblastoma Multiforme Millennium Pharmaceuticals, Inc. June 2009 Phase 1
NCT00667394 Completed Glioblastoma|Gliosarcoma|Anaplastic Astrocytoma|Anaplastic Oligodendroglioma|Anaplastic Mixed Oligoastrocytoma National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) April 2008 Phase 2
NCT00379080 Completed Adult Brain Tumor|Adult Giant Cell Glioblastoma|Adult Glioblastoma|Adult Gliosarcoma|Recurrent Adult Brain Tumor National Cancer Institute (NCI) January 2007 Phase 1|Phase 2
NCT00408902 Completed Clear Cell Renal Cell Carcinoma|Recurrent Renal Cell Cancer|Stage IV Renal Cell Cancer National Cancer Institute (NCI) November 2006 Phase 2
NCT00390468 Completed Metastatic Cancer|Pain|Prostate Cancer National Cancer Institute (NCI) October 2006 Phase 2
NCT00274248 Completed Acute Myelogenous Leukemia Millennium Pharmaceuticals, Inc. March 2005 Phase 1

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID