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

R406 (free base) Chemical Structure

CAS: 841290-80-0

规格 价格 库存 购买数量
10mM (1mL in DMSO) 2268.63 现货
10mg 2220.74 现货
50mg 7116.35 现货
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R406 (free base)相关产品

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
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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
FLT3 [1] Syk [1]
(Cell-free assay)
41 nM
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。

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)

体外溶解度
批次:

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

体内溶解度
批次:

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

摩尔浓度计算器

质量 浓度 体积 分子量

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

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,: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: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: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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