| 名稱 | Merestinib |
| 描述 | Merestinib (LY2801653) is an orally available, small molecule inhibitor of the proto-oncogene c-Met (Ki: 2 nM) with potential antineoplastic activity. Merestinib electively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met protein or expressing the constitutively activated c-Met protein. |
| 細胞實驗 | 2×103 DU145 cells/well on poly-D-lysine 96-well black/clear plates are treated with LY2801653 (in 0.4 % DMSO), immediately followed by the addition of human HGF (20 ng/ml), and incubated for 48 h at 37 °C. 2 % formaldehyde fixed cells are stained with AlexaFluor 488 Phalloidin and counterstained with Propidium Iodide. Colony counts are quantified on Acumen Explorer? laser-scanning fluorescence microplate cytometer. A colony is defined as≥4 cells.(Only for Reference) |
| 激酶實驗 | The Ki value and mode of inhibition of LY2801653 for the MET kinase activity are determined using a radiometric filter-binding assay. Reactions are carried out in 96-well plates in Enzyme dilution buffer (EDB) compose of 50 mM Tris HCl pH 7.5, 2 mM DTT, 0.005% Triton X-100, 10 mM MgCl2, and 250 ?M EDTA. Serially diluted LY2801653 (final concentration 250 to 0 nM) are followed by the addition of a series of 8 concentrations of 33P-γ-ATP (final concentration 400 to 10 μM ATP), and 5 nM enzyme (final concentration). After a 2-hour incubation, PolyGluTyr synthetic protein substrate (final 150 μg/mL) is added to initiate the 30-minute kinase reaction. Reactions are quenched with 10% H3PO4, transfer to a pre-wetted Multiscreen anionic phosphocellulose 96-well filter plate, and washed; radioactivity is measured with a scintillation counter. The experimental data are fit to a global mix model inhibition equation using GraphPad Prism softwar to generate an alpha value to determine the modality of inhibition and to calculate the Ki value for LY2801653[1]. |
| 體外活性 | Merestinib在體外展示對MET途徑依賴的細胞散布和細胞增殖的影響。在擁有MET基因擴增的細胞系(MKN45, Hs746T 和 H1993)中，Merestinib展現出更強的抗增殖活性，相較于沒有MET基因擴增的細胞系(U-87 mg, KATO-III)。Merestinib還針對13種每種都帶有單點突變的MET變體，保持了效力。此外，它對包括MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2以及絲氨酸/蘇氨酸激酶MKNK1/2在內的幾種其他受體酪氨酸激酶表現出強效活性。Merestinib抑制HGF激活的H460細胞中MET自磷酸化的平均IC50值為35.2±6.9 nM，而在S114細胞中MET自磷酸化的IC50為59.2 nM[1]。 |
| 體內活性 | Merestinib在多個異種移植模型中顯示出體內抗腫瘤效果，包括MET擴增(MKN45)、MET自分泌(U-87 mg、KP4)以及MET過表達(H441)；同時也表現出體內血管正?；?。該化合物能夠在異種移植腫瘤中誘導血管正常化。在所研究的物種中，Merestinib在小鼠體內的消除半衰期最短，為2.9小時，與非人靈長類動物的14.3小時相比。目前，Merestinib正處于針對晚期癌癥患者的第一階段臨床試驗中[1]。 |
| 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./Shipping at ambient temperature. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : 93 mg/mL (168.32 mM), Sonication is recommended.
DMSO : 93 mg/mL (168.32 mM), Sonication is recommended.
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| 關鍵字 | ROSKinase | ROS Kinase | ROS | Met | Merestinib | LY-2801653 | LY 2801653 | Inhibitor | inhibit | HGFR | Fms like tyrosine kinase 3 | FLT3 | DiscoidinDomainReceptor(DDR) | DiscoidinDomainReceptor | Discoidin Domain Receptor (DDR) | Discoidin Domain Receptor | DDR | c-Met/HGFR | cMet/HGFR | c-Met | cMet | Cluster of differentiation antigen 135 | CD135 |
| 相關產品 | β-Carotene | Inosine | Tempone | Gilteritinib | Tempol | Ethyl cinnamate | Nintedanib | Sorafenib | Acetylcysteine | L-Ascorbic acid 2-phosphate trisodium | Cyanidin | Rifamycin S |
| 相關庫 | 抑制劑庫 | 經典已知活性庫 | 抗癌活性化合物庫 | 已知活性化合物庫 | 激酶抑制劑庫 | 抗氧化化合物庫 | 膜蛋白靶向化合物庫 | 免疫/炎癥分子化合物庫 | 藥物功能重定位化合物庫 | 酪氨酸激酶分子庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |