Pyridone 6
(Synonyms: 吡啶酮6) 目录号 : GC11525
A pan-JAK inhibitor
Cas No.:457081-03-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Kinase experiment [1]: | |
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Preparation Method |
Assay for Jak family protein kinase activity. Jak3, Tyk2, Jakl and Jak2 kinase domains with N-terminal 'Flag' affinity tags were expressed in Sf9 cells using standard baculovirus methods and purified by antiFlag aflinity chromatography, followed by gel filtration chromatography. Jak family tyrosine kinase activity was measured by detection of the tyrosine phosphorylated peptide amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH2 (S, hereafter) detected by homogenous time resolved fluorescence (HTRF) using a europium labeled antibody to phosphotyrosine (pY20). For determining the mode of inhibition of Pyridone 6 with respect to peptide substrate, y33P ATP was included in the assays and incorporated radioactivity was measured using SAM2.Assay methods for PKA, PKCa and cdk2. Cyclin E-Cyclin dependent kinase 2 (cdk2) complex was assayed by SPA using the biotinylated peptide PKTPKKAKKL. Bovine PKA catalytic subunit was assayed by SPA using the biotinylated peptide LRRASLG as a substrate.PKCa was assayed by SPA using the biotinylated peptide AAKIQASFRGHMARKK. |
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Applications |
Pyridone 6 inhibited Tyk2, Jak1, Jak2, Jak3 with IC50s of 1nM,15nM,1nM and 5nM, respectively. |
| Cell experiment [2]: | |
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Cell lines |
WIF-B cells |
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Preparation Method |
Incubated cells with the pan-JAK inhibitor pyridone 6 (P6, 1 uM) for two hours prior to OSM-Dex addition and assayed channel activity four days later. |
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Reaction Conditions |
1 uM for two hours |
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Applications |
P6 did not significantly affect TRPM7 current on its own, but blocked the current depression in response to OSM-Dex. |
| Animal experiment [3]: | |
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Animal models |
NC/Nga mice |
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Preparation Method |
Nanoparticles containing Pyridone 6 (2 mg/body) or empty nanoparticles as a negative control (C-nano) were dissolved in 0.1 ml saline and administered s.c. 1 d after Dfb ointment application; this treatment was repeated twice a week. |
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Dosage form |
Pyridone 6 (2 mg/body) s.c. |
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Applications |
Pyridone 6-nano strongly ameliorated AD in NC/Nga mice, exerting an effect comparable to that of betamethasone ointment, a commonly used drug. |
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References: [1]. Thompson JE, Cubbon RM, et,al. Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23. doi: 10.1016/s0960-894x(02)00106-3. PMID: 11934592. [2]. Ogunrinde A, Pereira RD, et,al. Hepatocellular differentiation status is characterized by distinct subnuclear localization and form of the chanzyme TRPM7. Differentiation. 2017 Jul-Aug;96:15-25. doi: 10.1016/j.diff.2017.06.001. Epub 2017 Jun 12. PMID: 28609676. [3]. Nakagawa R, Yoshida H, et,al.Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17. J Immunol. 2011 Nov 1;187(9):4611-20. doi: 10.4049/jimmunol.1100649. Epub 2011 Sep 28. PMID: 21957150. |
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Pyridone 6 inhibits Jak3 with K(I)=5 nM; Pyridone 6 also inhibits Jak family members Tyk2 and Jak2 with IC(50)=1 nM and Jak1 with IC(50)=15 nM. Pyridone 6 was tested as an inhibitor of 21 other protein kinases; it inhibited these kinases with IC(50)s ranging from 130 nM to 10 μM[1].
Pyridone 6 strongly inhibited Th2 and modestly inhibited Th1, whereas it enhanced Th17 development when present within a certain range of concentrations. This is mostly due to strong suppression of the IFN-γ/STAT1, IL-2/STAT5, and IL-4/STAT6 signaling pathways by Pyridone 6, which all inhibit Th17 differentiation, as well as modest suppression of IL-6/STAT3, which is essential for Th17 differentiation[2，5].
In mice, Mean outward current decreased by 44% in WIF-B hepatoma cells incubated with the established hepatic differentiating factors oncostatin M/dexamethasone for 1-8 days. Pre-incubation with pyridone 6, a pan-JAK inhibitor, blocked the current reduction[3]. Pyridone 6 blocks IL2 and IL4 dependent proliferation of CTLL cells and inhibits the phosphorylation of STAT5 as measured by Western blotting[1]. Pyridone 6 is a more sensitive and specific inhibitor of JAK-STAT3 activity compared with AG490 and potently inhibited the growth of primary myeloma cells and myeloma-derived cell lines grown on BMSCs[4]. Inhibition of JAK by pyridone 6 resulted in the suppression of STAT3 phosphorylation and secretion of a subset of chemokines and JAK-activating cytokines[6]. Cytomix-induced STAT1 activation was lower and CXCR3 ligand mRNA production was more sensitive to Pyridone 6 and AG-490 in asthmatic than nonasthmatic ASMCs, but CXCL10/CXCL11 release was inhibited by the same proportion[7].
References:
[1]. Thompson JE, Cubbon RM, et,al. Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23. doi: 10.1016/s0960-894x(02)00106-3. PMID: 11934592
[2]. Nakagawa R, Yoshida H, et,al. Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17. J Immunol. 2011 Nov 1;187(9):4611-20. doi: 10.4049/jimmunol.1100649. Epub 2011 Sep 28. PMID: 21957150.
[3]. Ogunrinde A, Pereira RD, et,al. Hepatocellular differentiation status is characterized by distinct subnuclear localization and form of the chanzyme TRPM7. Differentiation. 2017 Jul-Aug;96:15-25. doi: 10.1016/j.diff.2017.06.001. Epub 2017 Jun 12. PMID: 28609676.
[4]. Pedranzini L, Dechow T, et,al.Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells. Cancer Res. 2006 Oct 1;66(19):9714-21. doi: 10.1158/0008-5472.CAN-05-4280. PMID: 17018630.
[5]. Mangan PR, Harrington LE, et,al.Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006 May 11;441(7090):231-4. doi: 10.1038/nature04754. Epub 2006 Apr 30. PMID: 16648837.
[6]. Ohno T, Aoki H, et,al. Cytokine Profile of Human Abdominal Aortic Aneurysm: Involvement of JAK/STAT Pathway. Ann Vasc Dis. 2018 Mar 25;11(1):84-90. doi: 10.3400/avd.oa.17-00086. PMID: 29682112; PMCID: PMC5882349.
[7]. Tan X, Alrashdan YA, et,al. Airway smooth muscle CXCR3 ligand production: regulation by JAK-STAT1 and intracellular Ca2?. Am J Physiol Lung Cell Mol Physiol. 2013 Jun 1;304(11):L790-802. doi: 10.1152/ajplung.00356.2012. Epub 2013 Apr 5. PMID: 23564506.
吡啶酮 6 抑制 Jak3，K(I)=5 nM； Pyridone 6 还抑制 Jak 家族成员 Tyk2 和 Jak2，IC(50)=1 nM 和 Jak1，IC(50)=15 nM。吡啶酮 6 作为 21 种其他蛋白激酶的抑制剂进行了测试；它抑制这些激酶，IC(50) 范围为 130 nM 到 10 μM[1]。
吡啶酮 6 强烈抑制 Th2 并适度抑制 Th1，而当存在于一定浓度范围内时，它会增强 Th17 的发育。这主要是由于吡啶酮 6 对 IFN-γ/STAT1、IL-2/STAT5 和 IL-4/STAT6 信号通路的强烈抑制，它们都抑制 Th17 分化，以及对 IL-6/STAT3 的适度抑制, 这对于 Th17 的分化[2，5] 是必不可少的。
在小鼠中，WIF-B 肝癌细胞与已建立的肝分化因子制瘤素 M/地塞米松孵育 1-8 天后，平均外向电流降低了 44%。与泛 JAK 抑制剂吡啶酮 6 预孵育可阻断电流降低[3]。吡啶酮 6 阻断 CTLL 细胞的 IL2 和 IL4 依赖性增殖，并抑制 STAT5 的磷酸化，如通过蛋白质印迹法检测到的[1]。与 AG490 相比，吡啶酮 6 是一种更敏感、更特异的 JAK-STAT3 活性抑制剂，可有效抑制骨髓间充质干细胞上生长的原代骨髓瘤细胞和骨髓瘤衍生细胞系的生长[4]。吡啶酮 6 对 JAK 的抑制导致趋化因子和 JAK 激活细胞因子子集的 STAT3 磷酸化和分泌受到抑制[6]。与非哮喘 ASMC 相比，Cytomix 诱导的 STAT1 激活较低，CXCR3 配体 mRNA 生成对吡啶酮 6 和 AG-490 更敏感，但 CXCL10/CXCL11 释放受到相同比例的抑制[7]。
| Cas No. | 457081-03-7 | SDF | |
| 别名 | 吡啶酮6 | ||
| 化学名 | 2-(tert-butyl)-9-fluoro-1H-benzo[h]imidazo[4,5-f]isoquinolin-7(6H)-one | ||
| Canonical SMILES | CC(C)(C)C(N1)=NC2=C1C3=C(C4=C2C=CNC4=O)C=C(F)C=C3 | ||
| 分子式 | C18H16FN3O | 分子量 | 309.34 |
| 溶解度 | ≥ 15.45 mg/mL in DMSO, ≥ 5.92 mg/mL in EtOH with ultrasonic and warming | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.2327 mL | 16.1634 mL | 32.3269 mL |
| 5 mM | 0.6465 mL | 3.2327 mL | 6.4654 mL |
| 10 mM | 0.3233 mL | 1.6163 mL | 3.2327 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells
Cancer Res2006 Oct 1;66(19):9714-21.PMID: 17018630DOI: 10.1158/0008-5472.CAN-05-4280
Interleukin-6 (IL-6) and the subsequent Janus-activated kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of multiple myeloma. Here, we compared the sensitivity and specificity of a novel pan-JAK inhibitor, tetracyclic pyridone 6 (P6), with that of AG490 in a panel of myeloma-derived cell lines. P6 induced growth arrest and subsequent apoptosis of the IL-6-dependent hybridoma and myeloma-derived cell lines (B9 and INA-6) grown either in IL-6-containing medium or in the presence of bone marrow-derived stromal cells (BMSC) using much lower concentrations of drug and with significantly faster kinetics than AG490. Myeloma-derived cell lines, which either express constitutively activated JAK/signal transducers and activators of transcription (STAT) 3 (U266) or are IL-6 growth stimulated (KMS11), are partially growth inhibited by P6. However, P6 does not inhibit the growth of myeloma-derived cell lines lacking activated JAKs/STATs nor does it inhibit mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase activity compared with AG490, which led to activation of ERK and induced robust apoptosis of all the examined cell lines. Finally, P6 inhibited the growth of primary myeloma patient samples grown in the presence of BMSCs. Thus, P6 is a more sensitive and specific inhibitor of JAK-STAT3 activity compared with AG490 and potently inhibited the growth of primary myeloma cells and myeloma-derived cell lines grown on BMSCs.
Pyridone 6, a pan-Janus-activated kinase inhibitor, suppresses osteoclast formation and bone resorption through down-regulation of receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced c-Fos and nuclear factor of activated T cells (NFAT) c1 expression
Biol Pharm Bull2009 Jan;32(1):45-50.PMID: 19122279DOI: 10.1248/bpb.32.45
It has been reported that Janus tyrosine kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of numerous malignancies and immune reactions, and inhibition of JAK has been implicated in cell growth inhibition. The role which JAK has on osteoclast differentiation and anti-bone resorptive activity is not well understood. In this study, we investigated the effects of a pan-JAK inhibitor, pyridone 6, on osteoclast differentiation and bone-resorption in vitro and ex vivo. Pyridone 6 inhibited osteoclast differentiation in mouse bone marrow macrophage (BMM) cultures stimulated by the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) and co-cultures of bone marrow cells and osteoblasts. Pyridone 6 suppressed the expression of c-Fos and nuclear factor of activated T cells (NFAT) c1 in BMMs. It also inhibited the bone resorptive activity of mature osteoclasts that was accompanied by disruption of actin rings. Pyridone 6 also suppressed I-kappaB degradation and extracellular signal-regulated kinase (ERK) in mature osteoclasts, suggesting that these are the key molecules that pyridone 6 targets in the inhibition of osteoclast function. These results demonstrate inhibition of JAK may be useful for the treatment of bone-resorptive diseases, such as osteoporosis.
Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17
J Immunol2011 Nov 1;187(9):4611-20.PMID: 21957150DOI: 10.4049/jimmunol.1100649
Atopic dermatitis (AD) is a common pruritic inflammatory disease triggered by a defective skin barrier and immunodysregulation. AD has been considered a typical example of a Th2 response associated with allergic disease. In the early phases of the disease, symptoms include IgE hyperproduction, eosinophil accumulation, and mast cell activation; in the chronic phase, a Th1-dominant immune response is also observed at the sites of AD skin lesions. The role of IL-17-producing Th (Th17) cells in AD has not been established. In the current study, we found that pyridone 6 (P6), a pan-JAK inhibitor, delayed the onset and reduced the magnitude of skin disease in an AD-like skin-disease model of NC/Nga mice. P6 reduced IFN-¦àand IL-13, whereas it enhanced IL-17 and IL-22 expression. In vitro, P6 also inhibited both Th1 and Th2 development, whereas it promoted Th17 differentiation from naive T cells when present within a certain range of concentrations. This was probably because P6 strongly inhibited STAT1, STAT5, and STAT6 phosphorylation, whereas STAT3 phosphorylation was less efficiently suppressed by P6 at the same concentration. Furthermore, IL-22 protects keratinocytes from apoptosis induced by IFN-¦ì and administration of IL-17 and IL-22 partially ameliorated skin diseases in NC/Nga mice. These results suggested that the JAK inhibitor P6 is therapeutic for AD by modulating the balance of Th2 and Th17.