| 名稱 | LY2109761 |
| 描述 | LY2109761 is a novel selective TGF-β receptor type I/II (TβRI/II) dual inhibitor with Ki of 38 nM and 300 nM, respectively; shown to negatively affect the phosphorylation of Smad2. |
| 細(xì)胞實(shí)驗(yàn) | LY2109761 cytotoxicity was determined by 3 methods: the MTT assay, manual counting of viable cells, and propidium iodide staining. MTT yields a purple formazan product that is detected using a 96-well plate reader at 570 nm. Cells were plated and cultured for 2 days in a 1% fetal bovine serum medium supplemented with LY2109761 at the following concentrations: 0.001, 0.01, 0.1, 1, 10, and 20 μM. Each experimental condition was reproduced in 8 wells, and each experiment was repeated 3 times. To confirm the cytotoxic data, cells were incubated under the described conditions and stained with the vital dye trypan blue, which does not react with the cell membrane because of its negative charge. All the unstained cells were counted using a hemocytometer. Four squares were counted for each condition, and each condition was repeated in triplicate in the same experiment. Each experiment was repeated 3 times for each cell line. Bars represent the average and standard deviation of all experiments. Under the same experimental conditions, nonpermeabilized cells were stained with propidium iodide and analyzed with a flow cytometer [2]. |
| 動物實(shí)驗(yàn) | Three days after the orthotopic implantation of 1.0 × 106 L3.6pl/GLT tumor cells in 50 μL of HBSS, when bioluminescence imaging confirmed that tumors were well established, 40 mice were randomly allocated into four groups (n = 10 mice per group) to receive one of the following treatments. (a) Vehicle solution for 50 μL of LY2109761 twice a day p.o. (days 1–5 of each week) and 50 μL of sterile saline daily i.p. (days 2 and 5 of each week; control group). (b) LY2109761 (50 mg/kg) twice a day p.o. (days 1–5 of each week) and 50 μL of sterile saline daily i.p. (days 2 and 5 of each week). (c) Gemcitabine (25 mg/kg) daily i.p. (days 2 and 5 of each week) and p.o. vehicle for 50μL of LY2109761 twice a day (days 1–5 of each week). (d) LY2109761 (50 mg/kg) twice a day (days 1–5 of each week) and gemcitabine (25 mg/kg) daily i.p. (days 2 and 5 of each week). Treatments were continued for 4 wk. All mice were weighed weekly and observed for tumor growth. Tumor diameter was assessed with a Vernier caliper, and tumor volume (mm3) was calculated as d2 × D/2, wherein d and D represent the shortest and longest diameters, respectively. Bulky disease was considered present when the tumor burden was prominent in the mouse abdomen (tumor volume, ≥2,000 mm3). When at least 6 of 10 mice in a treatment group presented with bulky disease, the median survival duration for that group was considered to be reached. At the median survival duration of the control group, the tumor growth in mice in all groups was evaluated using the bioluminescence emitted by the tumor cells. Bioluminescence imaging was conducted using a cryogenically cooled IVIS 100 imaging system coupled to a data acquisition computer running Living Image software. The mice were sacrificed by carbon dioxide inhalation when evidence of advanced bulky disease was present. The day of sacrifice was considered the day of death for survival evaluation [1]. |
| 體外活性 | 以LY2109761 (5 μM) 針對TβRI/II激酶活性幾乎完全抑制了L3.6pl/GLT細(xì)胞的基礎(chǔ)遷移率（P = 0.0107）及TGF-β1刺激下的遷移（P < 0.0001），表明L3.6pl/GLT細(xì)胞的體外遷移主要由內(nèi)源性TGF-β驅(qū)動[1]。LY2109761 (0.001-0.1 μM) 顯著上調(diào)E-cadherin mRNA及蛋白水平（P < 0.001），增加的E-cadherin主要定位于細(xì)胞膜，介導(dǎo)細(xì)胞間的錨定作用[2]。LY2109761 (10 μM) 或單獨(dú)輻射 (4 Gy) 均能降低NMA-23細(xì)胞的神經(jīng)球形成效率。LY2109761與輻射的聯(lián)合應(yīng)用在神經(jīng)球形成和限制稀釋實(shí)驗(yàn)中顯示出超加性效應(yīng)[3]。 |
| 體內(nèi)活性 | LY2109761 (50 mg/kg, p.o.) 顯著減小了腫瘤體積，并將小鼠的中位生存時(shí)間延長至45.0天，但差異并不顯著。僅當(dāng)LY2109761與gemcitabine聯(lián)合使用時(shí)，腫瘤體積(P < 0.05)和中位生存時(shí)間顯著受到影響，后者增加至77.5天(P = 0.0018) [1]。在一種原位顱內(nèi)模型中，LY2109761顯著減緩了腫瘤增長，延長了生存期，并延長了放射治療引起的生存期延長。組織學(xué)分析表明，LY2109761抑制了放射促進(jìn)的腫瘤侵襲，減少了腫瘤微血管密度，并減輕了間質(zhì)轉(zhuǎn)換 [3]。 |
| 存儲條件 | store at low temperature | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 6.88 mg/mL (15.57 mM)
Ethanol : Insoluble
H2O : Insoluble
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| 關(guān)鍵字 | TGF-β Receptor | Transforming growth factor beta receptors | Autophagy | Inhibitor | inhibit | LY 2109761 | LY2109761 | LY-2109761 |
| 相關(guān)產(chǎn)品 | Guanidine hydrochloride | Naringin | Valproic Acid | Taurine | Gefitinib | Aceglutamide | Hydroxychloroquine | Curcumin | Stavudine | Salicylic acid | Paeonol | Sodium 4-phenylbutyrate |
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