JAK3- in -11 (Compound 12) 是一种有效的、无细胞毒性、不可逆、具有口服活性的JAK3抑制剂，IC50值为1.7 nM，具有优良的选择性(高于其他 JAK3 亚型的588倍)，共价结合到 JAK3 的 ATP-binding pocket。 JAK3-IN-11 强烈抑制 JAK3 依赖的信号转导和T细胞增殖，是研究自身免疫性疾病的有效工具。
| 生物活性 | JAK3-IN-11 (Compound 12), a potent, noncytotoxic, irreversible, orally activeJAK3inhibitor withIC50value of 1.7 nM, has excellent selectivity (>588-fold compared to otherJAKisoforms), covalently bind to the ATP-binding pocket inJAK3. JAK3-IN-11 strongly inhibits JAK3-dependent signaling and T cell proliferation, is a promising tool for studyautoimmunediseases[1]. |
| IC50& Target[1] | JAK3 1.7 nM (IC50) | JAK2 1 μM (IC50) | JAK1 1.32 μM (IC50) |
|
体外研究
(In Vitro) | JAK3-IN-11 (Compound 12) (10 μM, 72 h) has no obvious cytotoxicity at a concentration of 10 μM[1].
JAK3-IN-11 (Compound 12) (72 h) displays strong inhibition for T cell proliferation with IC50values of 0.83 μM (anti-CD3/CD28 stimulation) and 0.77 μM (IL-2 stimulation)[1].
JAK3-IN-11 (Compound 12) (0-10 μM, 1h) abrogates IL-2 or IL-15-induced phosphorylation of STAT5 in a concentration-dependent manner[1].
JAK3-IN-11 (Compound 12) covalently binds to JAK3 and irreversibly inhibits JAK3[1].
Cell Proliferation Assay[1] | Cell Line: | Mouse T cells in complete RPMI1640 medium then exposed to anti-CD3/anti-CD28 or IL-2. | | Concentration: | | | Incubation Time: | 72 h. | | Result: | Displayed strong inhibition for T cell proliferation with an IC50values of 0.83 μM (anti-CD3/CD28 stimulation) and 0.77 μM (IL-2 stimulation), showed obvious significant immunosuppressive activity under selective inhibition of JAK3. |
Western Blot Analysis[1] | Cell Line: | Purified T cells were pre-activated coated with anti-CD3 and anti-CD28 for 72 h, then cultured with IL-2 (50 U/mL) for 36 h, then, cultured without IL-2 for 36 h | | Concentration: | 0.01, 0.1, 1, 10 μM. | | Incubation Time: | 1 h. | | Result: | Abrogated IL-2 or IL-15-induced phosphorylation of STAT5 in a concentration-dependent manner. |
|
体内研究
(In Vivo) | JAK3-IN-11 (Compound 12) (Oxazolone (OXZ)-induced DTH Balb/c mice; 0-30 mg/kg; PO, prior to and during the challenge phase, 6 days) inhibits oxazolone (OXZ)-induced delayed type hypersensitivity (DTH) responses in a dose-dependent manner[1].
| Animal Model: | Oxazolone (OXZ)-induced DTH Balb/c mice model[1]. | | Dosage: | 30, 10, and 3 mg/kg. | | Administration: | PO, prior to and during the challenge phase, 6 days. | | Result: | Inhibited oxazolone (OXZ)-induced delayed type hypersensitivity (DTH) responses in a dose-dependent manner. |
| Animal Model: | Male ICR mice[1]. | | Dosage: | 30 mg/kg for oral gavage, 10 mg/kg for intravenous administration. | | Administration: | Pharmacokinetic Analysis | | Result: | Preliminary pharmacokinetic data of JAK3-IN-11 (Compound 12) in male ICR Mice[1]
Male ICR mice, 30 mg/kg for oral gavage, 10 mg/kg for intravenous administration[1].
| Compound 12 | iv (10 mg/kg) | po (30 mg/kg) | | AUC(0-t) (mg/L*h)a | 1244.41 ± 77.83 | 889.42 ± 48.32 | | AUC(0-∞) (mg/L*h) | 1274.41 ± 57.18 | 897.12 ± 56.72 | | MRT (0-∞) (h)b | 0.73 ± 0.08 | 1.42 ± 0.38 | | Vz (L/kg)c | 8.36 ± 1.83 | 220.42 ± 24.71 | | CLz (L/h/kg)d | 8.15 ± 1.21 | 97.14 ± 20.87 | | t1/2(h)e | 0.47 ± 0.06 | 1.52 ± 0.34 | | Cmax(mg/L)f | 8763.23 ± 324.65 | 2008.21 ± 189.44 | | Bioavailability(%)g | | 23.82% |
a Area under the concentration time curve.
b Mean residence time.
c Volume in steady state.
d Plasma clearance.
e Terminal half-life.
f Peak plasma concentrations.
g Bioavailability = AUC0-t(po)/AUC0-t× 100%. |
|
| 分子量 | |
| Formula | |
| CAS 号 | |
| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
