| 名稱 | SLV-2436 |
| 描述 | SLV-2436 (SEL201-88) is a novel effective and ATP-competitive inhibitor of MNK1 and MNK2 (IC50: 10.8/5.4 nM). |
| 細(xì)胞實(shí)驗(yàn) | Western blot analysis. Cells were treated with dasatinib, imatinib, or SEL201 at the indicated times, and pellets were harvested to obtain protein extracts. Briefly, cell pellets were lysed in RIPA buffer (50 mM Tris-HCl, pH 8.0, with 150 mM sodium chloride, 1.0% Igepal CA-630 [NP-40], 0.5% sodium deoxycholate, and 0.1% SDS). After sonication, cell lysates were centrifuged at 15,871 g for 15 minutes. The supernatants were collected, and protein concentrations were quantified. Equal amounts of protein were loaded and separated on a 10% SDS-PAGE. After transferring to a nitrocellulose membrane (Bio-Rad), 5% milk/TBS was used to block for 1 hour, and then probed for target antibodies overnight at 4°C. After incubation with HRP-conjugated secondary antibodies for 1 hour at room temperature, the signals of targeted protein were developed with chemiluminescence substrate ECL Western blotting detection reagent. |
| 動(dòng)物實(shí)驗(yàn) | All animals were handled in strict accordance with the good animal practice and maintained according to the standards of pathogen-free conditions. The pharmacokinetic profile of SEL201 was assessed in 6-week-old female CD-1 mice (3 animals per time point). SEL201 was freshly dissolved in DMSO and then diluted in Captisol (Ligand) for administration with a volume of 10 μl per 1 g of body weight via the oral (p.o.; 5 mg/kg) or i.v. (2 mg/kg) route. Animals were sacrificed at 8 time points (5, 15, and 30 minutes and 1, 2, 4, 6, and 24 hours) and blood samples harvested. Plasma samples were collected and stored at –80°C for further analysis. To evaluate the pharmacodynamic properties of SEL201, 10- to 16-week-old male C57BL/6 mice (stock 000664, The Jackson Laboratory) were divided into a control group and 3 dosing groups. Animals were given either vehicle (DMSO + N,N-Dimethylacetamide + Captisol) or SEL201 at 10-, 25-, and 50-mg/kg doses (freshly dissolved). Drugs were administered p.o. in a volume of 10 μl per 1 g of body weight. Each animal received a total of 5 doses with the twice-daily schedule (i.e., every 12 hours). Body weight was assessed once daily. Six animals per experimental group supported sample collection at 2-time points (i.e., 4 hours and 24 hours) after the last, fifth administration, with 3 animals per time point. Plasma samples were collected and stored at –80°C for further analysis. For safety assessment of SEL201, 7- to 8-week-old tumor-bearing female Hsd: Athymic Nude-Foxn1nu mice (strain code 069, Envigo) were used. Before use, SEL201 was freshly dissolved, and doses of 50 mg/kg were administered twice daily p.o. in a volume of 10 μl per 1 g of body weight. Body weight was assessed every day. At the end of the experiment on day 37, mice were anesthetized and blood samples for total cell counts and biochemistry were obtained. |
| 體外活性 | 在體外激酶實(shí)驗(yàn)中，使用重組的MNK1和MNK2蛋白以及逐漸增加的SLV-2436濃度，結(jié)果表明SLV-2436具有高度活性，其IC50分別為MNK1的10.8納摩爾和MNK2的5.4納摩爾。為了確認(rèn)SLV-2436的激酶選擇性，進(jìn)行了1微摩爾濃度的KINOMEscan（DiscoverX）競(jìng)爭(zhēng)性結(jié)合實(shí)驗(yàn)，該實(shí)驗(yàn)包含了450種不同的激酶（32）。觀察到SLV-2436的結(jié)合譜顯著集中在包含MNK1和MNK2的CAMK激酶家族。 |
| 體內(nèi)活性 | 為探究SLV-2436的藥效學(xué)特性，對(duì)小鼠連續(xù)口服給藥5次，劑量分別為10、25和50 mg/kg，每12小時(shí)一次(即每天兩次)。在10 mg/kg的兩次日劑量下，第五次給藥后4小時(shí)，測(cè)定得到SLV-2436的低血漿濃度為125 ng/ml。然而，以25和50 mg/kg的劑量每天兩次給藥，相當(dāng)于每天SLV-2436的劑量為50和100 mg/kg，顯著增加了劑量依賴性的血漿暴露量，分別達(dá)到平均水平1,299 ng/ml和2,075 ng/ml。在24小時(shí)時(shí)間點(diǎn)，SLV-2436在血漿中仍可檢測(cè)到，三個(gè)劑量組（10、25和50 mg/kg每天兩次給藥）的劑量依賴性濃度分別為9、73和124 ng/ml。口服(p.o.)給藥SLV-2436，劑量為每天兩次的50 mg/kg，即每天100 mg/kg，連續(xù)37天，小鼠能夠良好耐受。此外，連續(xù)給藥37天，SLV-2436的劑量為每天100 mg/kg，未引起任何明顯的臨床毒性跡象。在研究終點(diǎn)進(jìn)行了包括血液學(xué)和生化參數(shù)在內(nèi)的血液化學(xué)檢查，并確認(rèn)了SLV-2436以每天100 mg/kg的劑量進(jìn)行多次給藥是安全的。盡管如此，SLV-2436表現(xiàn)出了良好的口服生物利用度，口服給藥后0.25小時(shí)達(dá)到最大血漿濃度1,078 ng/ml。 |
| 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 | DMSO : 50 mg/mL (142.53 mM)
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| 關(guān)鍵字 | MAP kinase interacting kinase | inhibit | SEL201 | MAPK interacting kinase | Mitogen activated protein kinase interacting kinase | SLV-2436 | Inhibitor | SEL 201 | MNK | SLV2436 |
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