| 名稱 | Capmatinib 2HCl |
| 描述 | Capmatinib 2HCl (INC-280 2HCl) is a novel, ATP-competitive inhibitor of c-MET kinase with an IC50 with 0.13 nM.Capmatinib 2HCl exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10, 000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, Capmatinib 2HCl potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. |
| 細(xì)胞實(shí)驗(yàn) | Cell lines: H441 cells. Concentrations: 0.24,1,4,16,63 nM. Incubation Time: 24 hours. Method:H441 cells are seeded in RPMI-1640 medium containing 10% FBS and grown to complete confluence.Gaps are introduced by scraping cells with a P200 pipette tip.Cells are then stimulated with 50 ng/mL recombinant human HGF to induce migration across the gap in the presence of various concentrations of INCB28060.After an overnight incubation,representative photographs are taken and a semiqualitative assessment of inhibition of cell migration is conducted. |
| 激酶實(shí)驗(yàn) | c-Met Kinase Assay:The assay buffer contains 50 mM Tris-HCl, 10 mM MgCl2, 100 mM NaCl, 0.1 mg/ml BSA, 5 mM DTT, pH 7.8. For HTS 0.8 μL of 5 mM of INCB28060 dissolved in DMSO are dotted on 384-well plates. DMSO titration suggests that the maximum tolerated concentration of the solvent is 4%. To measure IC50s the INCB28060 plate is prepared by 3-fold and 11-point serial dilutions. 0.8 μL of INCB28060 in DMSO is transferred from INCB28060 plate to the assay plate. The final concentration of DMSO is 2%. Solutions of 8 nM unphosphorylated c-Met or 0.5 nM phosphorylated c-Met are prepared in assay buffer. A 1 mM stock solution of peptide substrate Biotin-EQEDEPEGDYFEWLE-amide dissolved in DMSO is diluted to 1 μM in assay buffer containing 400 μM ATP (unphosphorylated c-Met) or 160 uM ATP (phosphorylated c-Met). A 20 μL volume of enzyme solution (or assay buffer for the enzyme blank) is added to the appropriate wells in each plate and then 20 μL/well of substrate solution to initiate the reaction. The plate is protected from light and incubated at 25 °C for 90 minutes. The reaction is stopped by adding 20 μL of a solution containing 45 mM EDTA, 50 mM Tris-HCl, 50 mM NaCl, 0.4 mg/ml BSA, 200 nM SA-APC and 3 nM EUPy20. The plate is incubated for 15-30 minutes at room temperature and HTRF (homogenous time resolved fluorescence) is measured on a Perkin Elmer Fusion α-FP instrument. The HTRF program settings used are as follows: Primary excitation filter 330/30, Primary window: 200 uSec, Primary delay: 50 uSec, Number of flashes: 15, Well read time: 2000 |
| 動(dòng)物實(shí)驗(yàn) | Animal Models: Eight-week-old female Balb/c nu/nu mice (Charles River) are inoculated subcutaneously with 4 × 106 tumor cells (S114 model) or with 5 × 106 tumor cells (U-87 mg glioblastoma model). Formulation: INCB28060 is prepared as a 5 mM stock solution in 100% dimethyl sulfoxide and routinely stored at room temperature. Dosages: 3,10,30 mg/kg. Administration: INCB28060 is orally dosed,twice each day. |
| 體外活性 | Capmatinib(free base) 在酶促活性方面表現(xiàn)出皮可摩爾級(jí)的效能，并且對(duì)于c-MET具有極高的特異性，其選擇性比人類大量激酶高出10000倍以上。Capmatinib抑制了人類c-MET的磷酸化和c-MET介導(dǎo)的癌細(xì)胞信號(hào)傳導(dǎo)。此外，Capmatinib阻止了依賴c-MET的細(xì)胞增殖和生存，避免了癌細(xì)胞在無(wú)基底的條件下生長(zhǎng)和細(xì)胞遷移。 |
| 體內(nèi)活性 | INCB28060（free base）在依賴c-MET的小鼠腫瘤模型中展現(xiàn)出強(qiáng)大的抗腫瘤活性，即使是0.03 mg/kg的口服劑量也能導(dǎo)致c-MET磷酸化約50%的抑制。在攜帶腫瘤的小鼠中觀察到了劑量依賴性的腫瘤生長(zhǎng)抑制。 |
| 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 : 11 mg/mL (22.66 mM)
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| 關(guān)鍵字 | Apoptosis | c-Met/HGFR | H441 | Capmatinib 2HCl | orally active | SNU-5 | INCB28060 | Inhibitor | INCB 28060 | S114 | INC280 | inhibit | INC 280 | Capmatinib | INCB-28060 | U-87MG | ATP competitive | INC-280 | Balb/c nu/nu mice |
| 相關(guān)產(chǎn)品 | Cabozantinib S-malate | Crizotinib | Amuvatinib | (±)-Norcantharidin | Capmatinib xHCl | Capmatinib | L-Ascorbic acid 2-phosphate trisodium | SGI-7079 | Bacitracin Zinc | AMG-458 |
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