R406 (free base)
R406 (free base) 是一种有效的Syk抑制剂，无细胞试验中IC50为41 nM，强效抑制Syk而不能抑制Lyn，对Flt3作用效果低5倍。R406 (free base) 可触发凋亡。Phase 1。
R406 (free base) Chemical Structure
CAS: 841290-80-0
产品质控
批次：
纯度：
99.95%
99.95
R406 (free base)相关产品
| 相关靶点 | ZAP70 | 点击展开 |
|---|---|---|
| 相关产品 | R406 PRT062607 (P505-15) HCl Entospletinib (GS-9973) Piceatannol BAY-61-3606 PRT-060318 2HCl TAK-659 Hydrochloride RO9021 | 点击展开 |
| 相关化合物库 | 酪氨酸激酶抑制剂分子库 PI3K/Akt 抑制剂库 血管生成相关化合物库 HIF-1信号通路化合物库 FDA抗癌药物库 | 点击展开 |
相关信号通路图
细胞实验数据示例
| 细胞系 | 实验类型 | 给药浓度 | 孵育时间 | 活性描述 | 文献信息 |
|---|---|---|---|---|---|
| Rec1 | Function assay | 2.5 uM | 6 hrs | Inhibition of Syk phosphorylation in human Rec1 cells at 2.5 uM incubated for 6 hrs by Western blotting method | 25222877 |
| Rec1 | Function assay | 2.5 uM | 6 hrs | Inhibition of Lyn phosphorylation in human Rec1 cells at 2.5 uM incubated for 6 hrs by Western blotting method | 25222877 |
| Rec1 | Function assay | 2.5 uM | 6 hrs | Inhibition of BTK phosphorylation in human Rec1 cells at 2.5 uM incubated for 6 hrs by Western blotting method | 25222877 |
| MV411 | Function assay | 72 hrs | Inhibition of Flt3 in human MV411 cells assessed as assessed as proliferation after 72 hrs incubation by spectrophotometry, EC50=0.01μM | 24779514 | |
| TF1 | Function assay | 1 hr | Inhibition of Jak2 in erythropoietin-stimulated human TF1 cells assessed as assessed as phospho-Stat5 after 1 hr incubation, EC50=0.013μM | 24779514 | |
| SK-M-MC | Function assay | 1 hr | Inhibition of Ret in human SK-M-MC cells assessed as assessed as phosphorylation after 1 hr incubation, EC50=0.036μM | 24779514 | |
| mast cells | Function assay | 1 hr | Inhibition of cKit in stem cell factor-stimulated bone marrow derived mouse mast cells assessed as phosphorylation after 1 hr incubation, EC50=0.046μM | 24779514 | |
| B-cells | Function assay | 1 hr | Inhibition of Syk in alphaIgM-stimulated human B cells assessed as cell proliferation after 1 hr incubation by flow cytometry, EC50=0.151μM | 24779514 | |
| B-cells | Function assay | 1 hr | Inhibition of Syk in alphaIgM-stimulated human B cells assessed as CD86 expression after 1 hr incubation by flow cytometry, EC50=0.335μM | 24779514 | |
| neutrophils cells | Function assay | Inhibition of SYK in human neutrophils cells assessed as reduction in FcepsilonR1/FcgammaR-mediated signaling responses, EC50=0.033μM | 22257213 | ||
| B-cells | Function assay | Inhibition of SYK in human B-cells cells assessed as reduction in FcepsilonR1/FcgammaR-mediated signaling responses, EC50=0.048μM | 22257213 | ||
| Ramos cells | Function assay | Inhibition of Syk in antihuman IgM-stimulated human Ramos cells assessed as decrease in BCR-mediated BLNK phosphorylation by cellular assay, EC50=0.053μM | 24779514 | ||
| mesangial cells | Function assay | Inhibition of SYK in cultured human mesangial cells assessed as reduction in FcepsilonR1/FcgammaR-mediated signaling responses, EC50=0.056μM | 22257213 | ||
| SK-N-SH | Function assay | Inhibition of Ret in human SK-N-SH cells, EC50=0.08μM | 22257213 | ||
| bone marrow cells | Function assay | Inhibition of IL3 dependent proliferation in C57/B16 mouse bone marrow cells using [3H]thymidine by liquid scintillation counting, IC50=0.147μM | 24726806 | ||
| THP1 | Function assay | Inhibition of SYK in human THP1 cells assessed as reduction in FcepsilonR1/FcgammaR-mediated signaling responses, EC50=0.171μM | 22257213 | ||
| Ramos | Function assay | Inhibition of Syk in anti IgM-stimulated human Ramos cells assessed as BLNK phosphorylation by cellular assay, IC50=0.457μM | 24726806 | ||
| SJ-GBM2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells | 29435139 | ||
| A673 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | ||
| SK-N-MC | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells | 29435139 | ||
| NB-EBc1 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells | 29435139 | ||
| Saos-2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells | 29435139 | ||
| OHS-50 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells | 29435139 | ||
| Rh41 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells | 29435139 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | R406 (free base) 是一种有效的Syk抑制剂，无细胞试验中IC50为41 nM，强效抑制Syk而不能抑制Lyn，对Flt3作用效果低5倍。R406 (free base) 可触发凋亡。Phase 1。 | ||||
|---|---|---|---|---|---|
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | R406是ATP竞争性Syk抑制剂，Ki为30 nM。在不同细胞中R406选择性抑制 Syk依赖的信号通路，EC50为33 nM 到171 nM,比作用于 Syk非依赖性通路效果高很多。[1] R406作用于多种弥漫性巨大细胞淋巴瘤，抑制细胞增殖，EC50 为0.8 μM 到 8.1 μM。1 μM 或 4 μM R406处理DLBCL细胞系，诱导caspases 9 和3激活, 而不激活caspase 8，导致大部分细胞凋亡。用R406预处理B细胞受体(BCR)交联的对R406 敏感的DLBCLs，完全抑制 SYK525/526磷酸化和BLNK依赖SYK的磷酸化。[2] R406有效降低MMP-9 mRNA水平，处理24和48小时，比对照组分别降低2.8和4.3倍,并降低RL细胞侵袭能力。[3] | |||
|---|---|---|---|---|
| 激酶实验 | 体外荧光偏振激酶实验 | |||
| R406在DMSO中连续稀释，然后在激酶buffer(20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg/mL 乙酰化BGG)中稀释到DMSO浓度为1%。室温下加入溶于激酶buffer的ATP和底物, 终DMSO浓度为0.2%。在含 5 μM HS1肽底物 和4 μM ATP的混合物中进行激酶反应，终体积为20 μL，在激酶buffer中加入0.125 ng Syk 开始反应。反应在室温下进行40分钟。加入20 μL 含EDTA/磷酸抗体(1X)/荧光蛋白磷酸肽示踪(0.5X)（在FP稀释buffer中稀释）的PTK猝灭混合物终止反应。然后实验板在室温下黑暗温育30分钟，然后在Polarion荧光偏振读数板上进行读数。R406按11种浓度进行平行实验，使用Prism GraphPad 软件通过回归曲线分析进行曲线拟合而测定IC50值。 | ||||
| 细胞实验 | 细胞系 | DHL4, DHL6, DHL8, DHL10, Wsu-NHL, Karpas422 (K422), OCI LY1, LY3, LY4, LY7, LY10, LY18, LY19, Pfeiffer, 和 Toledo | ||
| 浓度 | 溶于DMSO，浓度为10 mM,终浓度为5 μM | |||
| 孵育时间 | 72或96小时 | |||
| 方法 | 用连续稀释的R406 (0.3, 0.6, 1.25, 2.5, 或5 μM) 处理DLBCL 细胞系72 或 96小时。通过MTT实验测定细胞增殖，使用annexin V–FITC/碘化丙啶(PI)染色测定细胞凋亡。为了测定caspase9，8和3，细胞裂解，通过聚丙烯酰胺凝胶电泳（PAGE）进行大小分离，然后进行免疫印迹。 |
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| 体内研究(In Vivo) | ||
| 体内研究活性 | R406有效作用于多种免疫系统紊乱的动物模型。R406口服给药患免疫复合物导致炎症反应的小鼠，显著抑制皮肤反向被动Arthus反应，按1 mg/kg和 5 mg/kg剂量处理, 与对照组相比则抑制分别为72% 和86%。R406按 10 mg/kg 剂量处理用胶原抗体处理的鼠，显著降低炎症和肿胀, 使渐进性关节炎降低到较低水平，且延迟发病，且作用于K/BxN血清转移小鼠模型，降低临床关节炎达 50% 。[1] | |
|---|---|---|
| 动物实验 | Animal Models | 静脉注射 1% 卵清蛋白(OVA)的雌性C57BL/6 小鼠，卵清蛋白 (OVA)溶于含1% Evans 蓝染料的盐水(10 mg/kg)中;携带抗胶原抗体诱导型关节炎的雌性Balb/c小鼠；腹腔注射成年K/BxN鼠血清而诱发关节炎的雌性 C57BL/6小鼠 |
| Dosages | ~10 mg/kg/day | |
| Administration | 口服处理 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT01725230 | Completed | Rheumatoid Arthritis |
AstraZeneca |
November 2012 | Phase 1 |
| NCT01598571 | Completed | Healthy |
AstraZeneca |
May 2012 | Phase 1 |
| NCT01387308 | Completed | Healthy |
AstraZeneca |
August 2011 | Phase 1 |
| NCT01355354 | Completed | Healthy Volunteers|Rheumatoid Arthritis |
AstraZeneca |
June 2011 | Phase 1 |
化学信息&溶解度
| 分子量 | 470.45 | 分子式 | C22H23FN6O5 |
| CAS号 | 841290-80-0 | SDF | Download R406 (free base) SDF |
| Smiles | CC1(C(=O)NC2=C(O1)C=CC(=N2)NC3=NC(=NC=C3F)NC4=CC(=C(C(=C4)OC)OC)OC)C | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 29 mg/mL ( (61.64 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Water : Insoluble Ethanol : Insoluble |
摩尔浓度计算器 |
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体内溶解配方 现配现用，请按从左到右的顺序依次添加，澄清后再加入下一溶剂 |
动物体内配方计算器 | |||||
实验计算
动物体内配方计算器（澄清溶液）
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）
mg/kg
g
μL
只
第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系Selleck为您提供正确的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
计算结果：
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，注：如该浓度超过该批次药物DMSO溶解度，请先联系Selleck）；
体内配方配制方法：取μL DMSO母液，加入μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入μL ddH2O，混匀澄清。
体内配方配制方法：取μL DMSO母液，加入μL Corn oil，混匀澄清。
注意：1. 首先保证母液是澄清的；
2.一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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