| 名稱 | Baricitinib phosphate |
| 描述 | Baricitinib phosphate (INCB028050) is a selective orally bioavailable JAK1/JAK2 inhibitor. |
| 細(xì)胞實(shí)驗(yàn) | 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(shí)驗(yàn) | 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 | 在細(xì)胞基礎(chǔ)實(shí)驗(yàn)中，Baricitinib (INCB028050) 顯示出強(qiáng)大的JAK信號(hào)傳導(dǎo)和功能的抑制作用。在PBMCs中，Baricitinib 抑制了由IL-6刺激的典型底物STAT3 (pSTAT3)的磷酸化和隨后的趨化因子MCP-1的產(chǎn)生，其IC50值分別為44 nM和40 nM。在分離的天真T細(xì)胞中，INCB028050 同樣抑制了由IL-23刺激的pSTAT3（IC50=20 nM）。重要的是，這種抑制阻止了由Th17細(xì)胞生產(chǎn)的兩種病原性細(xì)胞因子（IL-17和IL-22）的產(chǎn)生，Th17細(xì)胞是具有明顯炎癥和病原性特征的輔助T細(xì)胞亞型，其IC50值為50 nM。與此形成鮮明對(duì)比的是，結(jié)構(gòu)相似但無效的JAK1/2抑制劑INCB027753和INCB029843在濃度高達(dá)10 μM的測(cè)試中，在任何這些實(shí)驗(yàn)系統(tǒng)中均無顯著效果[1]。 |
| 體內(nèi)活性 | Baricitinib (INCB028050) 的治療與對(duì)照組相比，在2周的治療期內(nèi)，以1 mg/kg的劑量抑制了后爪體積增加50%，而以3或10 mg/kg的劑量則抑制超過95%。由于在治療第0天，即動(dòng)物出現(xiàn)明顯病征時(shí)對(duì)爪體積的基線測(cè)量，對(duì)于那些在腫脹明顯好轉(zhuǎn)的動(dòng)物，抑制率可能超過100%[1]。Baricitinib (0.7 mg/天)處理的小鼠，通過H&E染色評(píng)估，表現(xiàn)出明顯減少的炎癥，CD8浸潤(rùn)減少，以及MHC I類和II類表達(dá)降低，與對(duì)照組相比有顯著差異。在與對(duì)照組相比，Baricitinib處理的小鼠中，對(duì)于鼠和人類斑禿(AA)疾病中關(guān)鍵的效應(yīng)細(xì)胞CD8+NKG2D+細(xì)胞大幅減少[2]。 |
| 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 (106.52 mM)
|
| 關(guān)鍵字 | LY-3009104 | inhibit | INCB-028050 Phosphate | Janus kinase | JAK | Baricitinib phosphate | Baricitinib | LY 3009104 Phosphate | INCB-028050 | LY-3009104 Phosphate | Inhibitor | LY 3009104 | Baricitinib Phosphate | INCB 028050 Phosphate | INCB028050 Phosphate | LY3009104 Phosphate | INCB 028050 |
| 相關(guān)產(chǎn)品 | JAK-IN-10 | Deucravacitinib | Gefitinib | Ruxolitinib | Ruxolitinib phosphate | Ibrutinib | Delgocitinib |
| 相關(guān)庫 | 經(jīng)典已知活性庫 | 抗癌上市藥物庫 | 已知活性化合物庫 | EMA 上市藥物庫 | 激酶抑制劑庫 | 抗衰老化合物庫 | FDA 上市藥物庫 | 抗病毒庫 | FDA 上市激酶抑制劑庫 | 抗癌藥物庫 |