Tandutinib (MLN518)

製品コードS1043 バッチS104310

印刷

化学情報

Chemical Structure Synonyms CT 53518, NSC726292, MLN518 Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C31H42N6O4
分子量 562.7 CAS No. 387867-13-2
Solubility (25°C)* 体外 Ethanol 100 mg/mL (177.71 mM)
DMSO 35 mg/mL (62.2 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
0.5% methylcellulose
10.0mg/ml Taking the 1 mL working solution as an example, take 10 mg of this product, add it to 1 ml of 0.5% methylcellulose clear solution, and mix evenly to form a uniform suspension. The mixed solution should be used immediately for optimal results. 
* <1 mg/ml means slightly soluble or insoluble.
* 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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 Tandutinib (MLN518, CT53518, NSC726292) 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.
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]

プロトコル(参考用のみ)

キナーゼアッセイ 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.
細胞アッセイ 細胞株 Ba/F3, Molm-13, Molm-14, HL60, AML193, KG-1, KG-1a, THP-1, and RS4;11
濃度 Dissolved in DMSO, final concentrations ~30 μM
反応時間 ~7 days
実験の流れ 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.
動物実験 動物モデル Female athymic nude (nu/nu) mice injected with Ba/F3 cells expressing W51 FLT3-ITD mutant
投薬量 40-120 mg/kg/day
投与方法 Orally by gavage

カスタマーフィードバック

Data from [Eur J Pharm Sci, 2013, 49(3), 441-50]

Data from [Data independently produced by Br J Cancer, 2012, 107, 1702-13]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma [ Cancer Cell, 2021, S1535-6108(21)00659-0] PubMed: 34971568
Extension of the Mechanistic Tissue Distribution Model of Rodgers and Rowland by Systematic Incorporation of Lysosomal Trapping: Impact on Unbound Partition Coefficient and Volume of Distribution Predictions in the Rat [ Drug Metab Dispos, 2021, 49(1):53-61] PubMed: 33148688
Comprehensive pharmacogenomic characterization of gastric cancer. [ Genome Med, 2020, 18;12(1):17] PubMed: 32070411
Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors. [ Cell Rep, 2019, 28(9):2331-2344] PubMed: 31461650
Small Molecule Amyloid-β Protein Precursor Processing Modulators Lower Amyloid-β Peptide Levels via cKit Signaling. [ J Alzheimers Dis, 2019, 67(3):1089-1106] PubMed: 30776010
MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation [ Cancer Cell, 2018, 34(2):315-330] PubMed: 30033091
Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6 [Uras IZ, et al. Blood, 2016, 127(23):2890-902] PubMed: 27099147
Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation [Huang A, et al. Cancer Lett, 2016, 377(2):149-57] PubMed: 27132990
Discovery and Rational Design of Pteridin-7(8H)-one-Based Inhibitors Targeting FMS-like Tyrosine Kinase 3 (FLT3) and Its Mutants. [ J Med Chem, 2016, 59(13):6187-200] PubMed: 27266526
Targeting a cell state common to triple-negative breast cancers [Muellner MK, et al. Mol Syst Biol, 2015, 11(1):789] PubMed: 25699542

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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