| 名稱 | Baricitinib |
| 描述 | Baricitinib (INCB028050) is a JAK1 and JAK2 inhibitor (IC50=5.9/5.7 nM) with selective and oral activity. Baricitinib has potential anti-inflammatory, immunomodulatory and anti-tumor activity. |
| 細胞實驗 | Baricitinib(INCB 028050) is dissolved in stock solutions, and then diluted with appropriate media before use[1]. Human PBMCs are isolated by leukapheresis followed by Ficoll-Hypaque centrifugation. For the determination of IL-6-induced MCP-1 production, PBMCs are plated at 3.3×105 cells per well in RPMI 1640+10% FCS in the presence or absence of various concentrations of INCB028050 (1 nM, 10 nM, 100 nM, 1 μM, and 10 μM). Following preincubation with compound for 10 min at room temperature, cells are stimulated by adding 10 ng/mL human recombinant IL-6 to each well. Cells are incubated for 48 h at 37°C, 5% CO2. Supernatants are harvested and analyzed by ELISA for levels of human MCP-1. The ability of INCB028050 to inhibit IL-6-induced secretion of MCP-1 is reported as the concentration required for 50% inhibition (IC50). Proliferation of Ba/F3-TEL-JAK3 cells is performed over 3 d using Cell-Titer Glo[1]. |
| 激酶實驗 | Enzyme assays are performed using a homogeneous time-resolved fluorescence assay with recombinant epitope tagged kinase domains (JAK1, 837-1142; JAK2, 828-1132; JAK3, 718-1124; Tyk2, 873-1187) or full-length enzyme (cMET and Chk2) and peptide substrate. Each enzyme reaction is performed with or without test compound (11-point dilution), JAK, cMET, or Chk2 enzyme, 500 nM (100 nM for Chk2) peptide, ATP (at the Km specific for each kinase or 1 mM), and 2.0% DMSO in assay buffer. The calculated IC50 value is the compound concentration required for inhibition of 50% of the fluorescent signal. Additional kinase assays are performed at Cerep using standard conditions at 200 nM. Enzymes tested included: Abl, Akt1, AurA, AurB, CDC2, CDK2, CDK4, CHK2, c-kit, EGFR, EphB4, ERK1, ERK2, FLT-1, HER2, IGF1R, IKKα, IKKβ, JNK1, Lck, MEK1, p38α, p70S6K, PKA, PKCα, Src, and ZAP70[1]. |
| 體外活性 | 方法: PBMC 細胞用 Baricitinib (0-10000 nM) 預孵育 10 min，加入 IL-6 (10 ng/mL) 刺激細胞 48 h，使用 ELISA assay 檢測相關(guān)因子。
結(jié)果: 在 PBMC 中，Baricitinib 抑制 IL-6 刺激的經(jīng)典底物 STAT3 的磷酸化以及隨后的趨化因子 MCP-1 的產(chǎn)生，IC50 值分別為 44 nM 和 40 nM。[1]
方法: CD19+ B 細胞用 IgM 抗體 (1 μg/mL)、sCD40L (250 ng/mL)、IL-4 (100 ng/mL) 和 Baricitinib (0.05-5 μM) 處理 2-5 天，使用 real-time PCR 檢測基因表達水平。
結(jié)果: 刺激兩天后，發(fā)現(xiàn) Baricitinib 以劑量依賴性方式顯著抑制 Aicda 的表達水平，而 Bcl6 的表達水平增加。刺激五天后，Xbp1 和 Irf4 的表達水平也顯著降低。在相同條件下從上清液中測量的 IgG 產(chǎn)生量顯著減少，這分別取決于刺激兩天和五天后 Baricitinib 劑量的增加。[2] |
| 體內(nèi)活性 | 方法: 為研究對自身免疫性關(guān)節(jié)炎的潛在治療效用，將 Baricitinib (1-10 mg/kg) 口服給藥給膠原誘導性關(guān)節(jié)炎 (CIA) 的 DBA/1j 小鼠，每天兩次，持續(xù) 15 天。
結(jié)果: 早在給藥后 4 天，疾病的臨床癥狀就得到了改善，在研究終止時，與載體對照組相比，臨床評分分別降低了 19%、67% 和 61%，這是劑量依賴性的。[1] |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 6.9 mg/mL (18.58 mM), Suspension. Please add co-solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately.
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 55 mg/mL (148.08 mM)
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| 關(guān)鍵字 | Inhibitor | JAK | Janus kinase | INCB-028050 | inhibit | Baricitinib | LY 3009104 | INCB 028050 | LY-3009104 |
| 相關(guān)產(chǎn)品 | JAK-IN-10 | Tofacitinib Citrate | Deucravacitinib | Gefitinib | Prexasertib | Ruxolitinib | CEP-33779 | Fedratinib | GSK 3 Inhibitor IX | Ruxolitinib phosphate | Ibrutinib | Delgocitinib |
| 相關(guān)庫 | 抗癌活性化合物庫 | 抗癌上市藥物庫 | 經(jīng)典已知活性庫 | 激酶抑制劑庫 | EMA 上市藥物庫 | 抗衰老化合物庫 | FDA 上市激酶抑制劑庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |