| 名稱 | Tandutinib |
| 描述 | Tandutinib (CT53518) (MLN518, CT53518), an effective FLT3 antagonist (IC50: 0.22 μM), can also inhibit c-Kit and PDGFR, 15-20 fold higher potency for FLT3 versus CSF-1R and >100-fold selectivity for the same target versus FGFR, EGFR, and KDR. |
| 細(xì)胞實(shí)驗(yàn) | 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) |
| 激酶實(shí)驗(yàn) | 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 15,000 g 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. |
| 體外活性 | 在攜帶表達(dá)W51 FLT3-ITD 突變型Ba/F3細(xì)胞的小鼠中,Tandutinib（60 mg/kg,2次/天,p.o.）可顯著延長(zhǎng)壽命, 而在小鼠骨髓移植模型中,其可使死亡率顯著降低.Tandutinib（180 mg/kg,2次/天）對(duì)正常造血功能有輕微毒性,作用于小鼠時(shí),對(duì)FLT3 ITD-陽(yáng)性的白血病有良好的治療效果. |
| 體內(nèi)活性 | 與星孢菌素不同,Tandutinib對(duì)βPDGF,FLT3和c-Kit自磷酸化具有較好的抑制效果（IC50：0.17-0.22 μM）, 但幾乎不影響EGFR, FGFR, KDR, InsR, Src, Abl, PKC, PKA和 MAPKs。由于對(duì)FLT3抑制的特異性,Tandutinib只對(duì)FLT3-ITD陽(yáng)性Molm-14細(xì)胞有效,對(duì)FLT3-ITD陰性THP-1細(xì)胞無(wú)效果,處理24和96 h,造成的細(xì)胞凋亡分別為51%和78%。與AML的ITD陰性患者相比,Tandutinib優(yōu)先抑制AML的FLT3 ITD陽(yáng)性患者體內(nèi)爆發(fā)式的集落生長(zhǎng),但對(duì)正常人祖細(xì)胞形成集落沒(méi)有影響。Tandutinib對(duì)不依賴IL-3的細(xì)胞生長(zhǎng)具有抑制作用,同時(shí)抑制FLT3-ITD自磷酸化（IC50：10-100 nM）。Tandutinib對(duì)含F(xiàn)LT3-ITD突變的人白血病Ba/F3細(xì)胞增殖也有抑制作用（IC50：10-30 nM）,還抑制FLT3-ITD-陽(yáng)性的Molm-13和14細(xì)胞（IC50：10 nM）。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : 6 mg/mL (10.66 mM)
DMSO : 50 mg/mL (88.86 mM)
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| 關(guān)鍵字 | CT-53518 | Acute | MLN 518 | FLT3-ITD | Inhibitor | NSC 726292 | inhibit | c-Kit | autophosphorylation | CD135 | CT 53518 | blood-brain | MLN-518 | FLT3 | myelogenous | leukemia | Fms like tyrosine kinase 3 | MAP | barrier | SCFR | PDGFR | Platelet-derived growth factor receptor | CD117 | Apoptosis | Cluster of differentiation antigen 135 | Tandutinib | NSC-726292 | PI3 |
| 相關(guān)產(chǎn)品 | Metronidazole | 5-Fluorouracil | Stavudine | Tributyrin | Dextran sulfate sodium salt (MW 4500-5500) | Myricetin | Sorafenib | L-Ascorbic acid | Sodium 4-phenylbutyrate |
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