R406 (free base)

目錄號：S1533 Purity: 99.95%

R406 (free base) 是一種有效的Syk抑制劑，無細(xì)胞試驗(yàn)中IC50為41 nM，強(qiáng)效抑制Syk而不能抑制Lyn，對Flt3作用效果低5倍。R406 (free base) 可觸發(fā)凋亡。Phase 1。

R406 (free base) Chemical Structure

CAS: 841290-80-0

規(guī)格	價(jià)格	庫存
10mM (1mL in DMSO)	2268.63	現(xiàn)貨
10mg	2220.74	現(xiàn)貨
50mg	7116.35	現(xiàn)貨
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產(chǎn)品質(zhì)控

批次：純度： 99.95%

99.95

R406 (free base)相關(guān)產(chǎn)品

相關(guān)靶點(diǎn)	ZAP70	點(diǎn)擊展開
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相關(guān)化合物庫	酪氨酸激酶抑制劑分子庫 PI3K/Akt 抑制劑庫血管生成相關(guān)化合物庫 HIF-1信號通路化合物庫 FDA抗癌藥物庫	點(diǎn)擊展開

細(xì)胞實(shí)驗(yàn)數(shù)據(jù)示例

細(xì)胞系	實(shí)驗(yàn)類型	給藥濃度	孵育時(shí)間	活性描述	文獻(xiàn)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
點(diǎn)擊查看更多細(xì)胞系數(shù)據(jù)

生物活性

產(chǎn)品描述

靶點(diǎn)

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

體外研究(In Vitro)
體外研究活性	R406是ATP競爭性Syk抑制劑，K_i為30 nM。在不同細(xì)胞中R406選擇性抑制 Syk依賴的信號通路，EC50為33 nM 到171 nM,比作用于 Syk非依賴性通路效果高很多。^[1] R406作用于多種彌漫性巨大細(xì)胞淋巴瘤，抑制細(xì)胞增殖，EC50 為0.8 μM 到 8.1 μM。1 μM 或 4 μM R406處理DLBCL細(xì)胞系，誘導(dǎo)caspases 9 和3激活, 而不激活caspase 8，導(dǎo)致大部分細(xì)胞凋亡。用R406預(yù)處理B細(xì)胞受體(BCR)交聯(lián)的對R406 敏感的DLBCLs，完全抑制 SYK525/526磷酸化和BLNK依賴SYK的磷酸化。^[2] R406有效降低MMP-9 mRNA水平，處理24和48小時(shí)，比對照組分別降低2.8和4.3倍,并降低RL細(xì)胞侵襲能力。^[3]
激酶實(shí)驗(yàn)	體外熒光偏振激酶實(shí)驗(yàn)
激酶實(shí)驗(yàn)	R406在DMSO中連續(xù)稀釋，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)中稀釋到DMSO濃度為1%。室溫下加入溶于激酶buffer的ATP和底物, 終DMSO濃度為0.2%。在含 5 μM HS1肽底物和4 μM ATP的混合物中進(jìn)行激酶反應(yīng)，終體積為20 μL，在激酶buffer中加入0.125 ng Syk 開始反應(yīng)。反應(yīng)在室溫下進(jìn)行40分鐘。加入20 μL 含EDTA/磷酸抗體(1X)/熒光蛋白磷酸肽示蹤(0.5X)（在FP稀釋buffer中稀釋）的PTK猝滅混合物終止反應(yīng)。然后實(shí)驗(yàn)板在室溫下黑暗溫育30分鐘，然后在Polarion熒光偏振讀數(shù)板上進(jìn)行讀數(shù)。R406按11種濃度進(jìn)行平行實(shí)驗(yàn)，使用Prism GraphPad 軟件通過回歸曲線分析進(jìn)行曲線擬合而測定IC50值。
細(xì)胞實(shí)驗(yàn)	細(xì)胞系	DHL4, DHL6, DHL8, DHL10, Wsu-NHL, Karpas422 (K422), OCI LY1, LY3, LY4, LY7, LY10, LY18, LY19, Pfeiffer, 和 Toledo
	濃度	溶于DMSO，濃度為10 mM,終濃度為5 μM
	孵育時(shí)間	72或96小時(shí)
	方法	用連續(xù)稀釋的R406 (0.3, 0.6, 1.25, 2.5, 或5 μM) 處理DLBCL 細(xì)胞系72 或 96小時(shí)。通過MTT實(shí)驗(yàn)測定細(xì)胞增殖，使用annexin V–FITC/碘化丙啶(PI)染色測定細(xì)胞凋亡。為了測定caspase9，8和3，細(xì)胞裂解，通過聚丙烯酰胺凝膠電泳（PAGE）進(jìn)行大小分離，然后進(jìn)行免疫印跡。

體內(nèi)研究(In Vivo)
體內(nèi)研究活性	R406有效作用于多種免疫系統(tǒng)紊亂的動物模型。R406口服給藥患免疫復(fù)合物導(dǎo)致炎癥反應(yīng)的小鼠，顯著抑制皮膚反向被動Arthus反應(yīng)，按1 mg/kg和 5 mg/kg劑量處理, 與對照組相比則抑制分別為72% 和86%。R406按 10 mg/kg 劑量處理用膠原抗體處理的鼠，顯著降低炎癥和腫脹, 使?jié)u進(jìn)性關(guān)節(jié)炎降低到較低水平，且延遲發(fā)病，且作用于K/BxN血清轉(zhuǎn)移小鼠模型，降低臨床關(guān)節(jié)炎達(dá) 50% 。^[1]
動物實(shí)驗(yàn)	Animal Models	靜脈注射 1% 卵清蛋白(OVA)的雌性C57BL/6 小鼠，卵清蛋白 (OVA)溶于含1% Evans 藍(lán)染料的鹽水(10 mg/kg)中;攜帶抗膠原抗體誘導(dǎo)型關(guān)節(jié)炎的雌性Balb/c小鼠；腹腔注射成年K/BxN鼠血清而誘發(fā)關(guān)節(jié)炎的雌性 C57BL/6小鼠
	Dosages	~10 mg/kg/day
	Administration	口服處理

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試驗(yàn)信息 (data from https://clinicaltrials.gov, updated on 2024-05-22)
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

參考文獻(xiàn)
[1] Braselmann S, et al. J Pharmacol Exp Ther, 2006, 319(3), 998-1008. [2] Chen L, et al. Blood, 2008, 111(4), 2230-2237. [3] Fruchon S, et al. Leukemia, 2011, 1-11.

參考文獻(xiàn)

[1] Braselmann S, et al. J Pharmacol Exp Ther, 2006, 319(3), 998-1008.
[2] Chen L, et al. Blood, 2008, 111(4), 2230-2237.
[3] Fruchon S, et al. Leukemia, 2011, 1-11.

化學(xué)信息&溶解度

分子量	470.45	分子式	C₂₂H₂₃FN₆O₅
CAS號	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
儲存條件(自收到貨起)	3年-20°C粉狀	儲備液保存和期限建議分裝儲備液，避免反復(fù)凍融！	1年-80°C溶于溶劑
儲存條件(自收到貨起)	3年-20°C粉狀	儲備液保存和期限建議分裝儲備液，避免反復(fù)凍融！	1個(gè)月-20°C溶于溶劑

體外溶解度
批次：

DMSO : 29 mg/mL ( (61.64 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO)

Water : Insoluble

Ethanol : Insoluble

DMSO : 21 mg/mL ( (44.63 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO)

Water : Insoluble

Ethanol : Insoluble

摩爾濃度計(jì)算器

體內(nèi)溶解度
批次：

現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑

動物體內(nèi)配方計(jì)算器

實(shí)驗(yàn)計(jì)算

摩爾濃度計(jì)算器

質(zhì)量	濃度	體積	分子量
=	×	×

稀釋計(jì)算器分子量計(jì)算器

動物體內(nèi)配方計(jì)算器（澄清溶液）

第一步：請輸入基本實(shí)驗(yàn)信息（考慮到實(shí)驗(yàn)過程中的損耗，建議多配一只動物的藥量）

給藥劑量 mg/kg 動物平均體重 g 每只動物給藥體積 μL 動物數(shù)量只

第二步：請輸入動物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）

% DMSO + % + % Tween 80 + % ddH2O

%DMSO+ %

計(jì)算結(jié)果：

工作液濃度： mg/ml；

DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；

體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH₂O，混勻澄清。

體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。

注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進(jìn)行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。

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C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
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C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):

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