| 名稱 | XL019 |
| 描述 | XL019 is a potent and selective JAK2 inhibitor with IC50 of 2.2 nM, 100 fold selectivity over JAK1. |
| 激酶實(shí)驗(yàn) | FRET-Based Z′-Lyte Assay Detecting Peptide Substrate Phosphorylation: The kinases ABL1, ABL1(E255K), ABL1 (G250E), ABL1(T315I), and ABL1(Y253F) are P3049, PV3864, PV3865, PV3866, and PV3863 are full-length human recombinant protein expressed in insect cells and histidine-tagged. Inhibition activities of inhibitors against Abl1 and its mutants are performed in 384-well plates using the FRET-based Z′-Lyte assay system. Briefly, the kinase substrate is diluted into 5 μL of kinase reaction buffer; and the kinase is added. Compounds (10 nL) with indicated concentrations are then delivered to the reaction by using Echo liquid handler, and the mixture is incubated for 30 min at room temperature. Then 5 μL of 2X ATP solution is added to initiate the reaction, and the mixture is further incubated for 2 h at room temperature. The resulting reactions contains 10 μM (for wild-type Abl1, and mutants Y253F, Q252H, M351T, and H396P) or 5 μM (for mutants E255K, G250E, T315I) of ATP, 2 μM of Tyr2 Peptide substrate in 50 mM HEPES (PH 7.5), 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 0.0247 μg/mL Abl1, and inhibitors as appropriate. Then, 5 μL of development reagent is added, and the mixture is incubated for 2 h at room temperature before 5 μL of stop solution is added. Fluorescence signal ratio of 445 nm (Coumarin)/520 nm (fluorescin) is examined on an EnVision Multilabel Reader. The data are analyzed using Graphpad Prism5. The data are the mean value of three experiments. |
| 體外活性 | XL019具有優(yōu)越的藥效學(xué)特性,并且表現(xiàn)出良好的口服吸收性,在不同物種中表現(xiàn)適中的清除率和半衰期.在給藥30,100和300 mg/kg XL019后,明顯抑制下游標(biāo)記pSTAT1和pSTAT3,導(dǎo)致pSTAT1的ED 50為42 mg/kg和pSTAT3的ED 50為210 mg/kg.XL019抑制小鼠HEL.92.1.7異種移植腫瘤生長,200 mg/kg和300 mg/kg XL019分別每天給藥兩次持續(xù)14天,表現(xiàn)60％和70％的抑制作用. |
| 體內(nèi)活性 | L019抑制JAK2以及突變形式JAK2V617F的激活,其可導(dǎo)致JAK-STAT信號(hào)傳導(dǎo)途徑的抑制并可誘導(dǎo)凋亡。與其他細(xì)胞系統(tǒng)相比,在EPO刺激紅細(xì)胞系后,XL019顯示出10倍以上的STAT5磷酸化選擇性抑制（IC50 = 64 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 | DMSO : 13 mg/mL (29.2 mM)
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
|
| 關(guān)鍵字 | Janus kinase | Apoptosis | antitumor,HEL.92.1.7 | Inhibitor | XL019 | cells | XL 019 | XL-019 | inhibit | JAK | selective | oral | phosphorylation | tumor |
| 相關(guān)產(chǎn)品 | L-Glutamic acid | Metronidazole | 5-Fluorouracil | Dextran sulfate sodium salt (MW 4500-5500) | Stavudine | Tributyrin | Myricetin | Sorafenib | L-Ascorbic acid | Acetylcysteine | Salicylic acid | Sodium 4-phenylbutyrate |
| 相關(guān)庫 | 抑制劑庫 | 經(jīng)典已知活性庫 | 已知活性化合物庫 | 激酶抑制劑庫 | 抗衰老化合物庫 | 膜蛋白靶向化合物庫 | 酪氨酸激酶分子庫 | 藥物功能重定位化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |