Xevinapant (AT406)

别名: ARRY-334543, Debio1143, SM-406

Xevinapant (AT406, ARRY-334543, Debio1143, SM-406)是一种有效的,拟Smac的IAP(通过E3泛素连接酶起作用的凋亡蛋白抑制剂)拮抗剂,与XIAP-BIR3, cIAP1-BIR3和cIAP2-BIR3结合,Ki为66.4 nM, 1.9 nM和5.1 nM,比作用于Smac AVPI肽亲和力高50到100倍。Phase 1。

Xevinapant (AT406) Chemical Structure

Xevinapant (AT406) Chemical Structure

CAS: 1071992-99-8

规格 价格 库存 购买数量
10mM (1mL in DMSO) RMB 1613.43 现货
5mg RMB 1367.73 现货
25mg RMB 4070.43 现货
200mg RMB 16134.3 现货
1g RMB 36609.3 现货
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客户使用Selleck的Xevinapant (AT406)发表文献34

产品质控

批次: 纯度: 99.96%
99.01

Xevinapant (AT406)相关产品

相关信号通路图

IAP抑制剂选择性比较

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
MDA-MB-231 Function assay 100 nM 15 mins Induction of degradation of cIAP1 in human MDA-MB-231 cells at 100 nM after 15 mins by Western blot analysis 21443232
MDA-MB-231 Apoptosis assay 1.5 uM 12 hrs Induction of apoptosis in human MDA-MB-231 cells assessed as activation of caspase-3 activity at 1.5 uM after 12 hrs by Western blot analysis 21443232
MDA-MB-231 Apoptosis assay 1.5 uM 12 hrs Induction of apoptosis in human MDA-MB-231 cells assessed as activation of PARP cleavage at 1.5 uM after 12 hrs by Western blot analysis 21443232
MDA-MB-231 Antitumor assay 30 mg/kg 2 weeks Antitumor activity against human MDA-MB-231 cells xenografted in SCID mouse assessed inhibition of tumor growth at 30 mg/kg, po administered daily for 5 days/week for 2 weeks 21443232
MDA-MB-231 Antitumor assay 100 mg/kg 2 weeks Antitumor activity against human MDA-MB-231 cells xenografted in SCID mouse assessed inhibition of tumor growth at 100 mg/kg, po administered daily for 5 days/week for 2 weeks 21443232
MDA-MB-231 Antitumor assay 100 mg/kg every 3 days Antitumor activity against human MDA-MB-231 cells xenografted in Balb/c SCID mouse assessed as tumor growth inhibition at 100 mg/kg, po qd measured every 3 days 26218264
MDA-MB-231 Function assay 10 nM Induction of degradation of cIAP1 in human MDA-MB-231 cells at 10 nM by Western blot analysis 21443232
SKOV3 Growth inhibition assay 4 days Growth inhibition of human SKOV3 cells after 4 days by WST8 assay, IC50 = 0.142 μM. 21443232
HEK293 Function assay 2 hrs Antagonist activity at full-length FLAG-tagged XIAP (unknown origin) transfected in HEK293 cells assessed as inhibition of interaction with caspase 9 after 2 hrs by immunoprecipitation assay, EC50 = 0.034 μM. 26218264
MDA-MB-231 Cytotoxicity assay 72 hrs Cytotoxicity against human sensitive MDA-MB-231 cells assessed as inhibition of cell growth after 72 hrs by Alamar Blue assay, EC50 = 0.019 μM. 26218264
EVSA-T Cytotoxicity assay 72 hrs Cytotoxicity against human sensitive EVSA-T cells assessed as inhibition of cell growth after 72 hrs by Alamar Blue assay, EC50 = 0.0021 μM. 26218264
MDA-MB-231 Growth inhibition assay 4 days Growth inhibition of human MDA-MB-231 cells after 4 days by WST8 assay, IC50 = 0.144 μM. 21443232
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells 29435139
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
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 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
LAN-5 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 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
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells 29435139
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells 29435139
点击查看更多细胞系数据

生物活性

产品描述 Xevinapant (AT406, ARRY-334543, Debio1143, SM-406)是一种有效的,拟Smac的IAP(通过E3泛素连接酶起作用的凋亡蛋白抑制剂)拮抗剂,与XIAP-BIR3, cIAP1-BIR3和cIAP2-BIR3结合,Ki为66.4 nM, 1.9 nM和5.1 nM,比作用于Smac AVPI肽亲和力高50到100倍。Phase 1。
靶点
cIAP1-BIR3 [1]
(cell-free assay)
cIAP2-BIR3 [1]
(cell-free assay)
XIAP-BIR3 [1]
(cell-free assay)
1.9 nM(Ki) 5.1 nM(Ki) 66.4 nM(Ki)
体外研究(In Vitro)
体外研究活性 AT-406是一种Smac模拟物,在氢键结合以及与XIAP的疏水性相互作用中,似乎能够很接近地模拟AVPI多肽,伴随额外的与XIAP的W323疏水性接触。AT-406对这些IAPs比对Smac AVPI多肽更敏感,具有50-100倍的结合亲和力。AT-406 (1 μM)完全恢复caspase-9的活性,其在无细胞体系中被500 nM XIAP BIR3抑制。在MDA-MB-231细胞中,AT-406诱导快速的细胞cIAP1降解,并摧毁细胞XIAP蛋白。AT-406有效抑制大量人癌症细胞系,在MDA-MB-231细胞和SK-OV-3卵巢癌细胞中,IC50分别为144和142 nM,对正常人乳腺样上皮MCF-12F细胞和初级人正常前列腺上皮细胞具有低毒性。在MDA-MB-231细胞中,AT-406通过诱导caspase-3活化和PARP裂解,诱导细胞凋亡。[1]
激酶实验 XIAP,cIAP1,和 cIAP2 BIR3 蛋白质的荧光偏振试验
FL-AT-406(荧光标记的AT-406)用于开发一组新的FP试验,用于测定Smac模拟物对XIAP,cIAP-1,和cIAP-2 BIR3蛋白质的结合亲和力。FL-AT-406对每种IAP蛋白质的Kd值通过滴定实验使用固定浓度的FL-AT-406和不同浓度直到饱和的蛋白质进行测定。荧光偏振值使用Infinite M-1000酶标仪在Microfluor296孔,黑色,圆底板中测量。对每个孔,加入FL-AT-406 (对XIAP BIR3,cIAP-1 BIR3,和cIAP-2 BIR3的实验分别为2,1,和1 nM)和不同浓度的蛋白质,在测定缓冲液(100 mM磷酸钾,pH 7.5,100 μg/mL牛γ-球蛋白,0.02%叠氮化钠,和4% DMSO)中终体积为125 μL。将板混合,并在室温下温和摇晃培育2-3小时。毫极化单元(mP)中的偏振值在485 nm激发波长和530 nm发射波长下测量。随后,平衡解离常数(Kd)使用Graphpad Prism 5.0软件,根据蛋白质浓度对剂量依赖性FP的增加通过S形曲线拟合进行计算。在XIAP3 BIR3的竞争性结合实验中,AT-406与20 nM XIAP BIR3蛋白质和2 nM FL-AT-406在试验缓冲液(100 mM磷酸钾,pH 7.5;100 μg/mL 牛γ-球蛋白;0.02% 叠氮化钠)中进行培育。在cIAP1 BIR3蛋白质竞争性结合实验中,使用3 nM蛋白质和1 nM FL-AT-406。对于cIAP2 BIR3竞争性结合实验,使用5 nM蛋白质和1 nM FL-AT-406。对每个竞争性结合实验,偏振值在培育2-3小时之后使用Infinite M-1000酶标仪测量。IC50值,50%结合示踪物被取代时的抑制剂浓度,根据绘图使用非线性最小二乘法分析计算。曲线拟合使用PRISM软件进行。计算AT-406的Ki值。
细胞实验 细胞系 MDA-MB-231乳腺癌和 SK-OV-3 卵巢癌细胞系
浓度 ~ 1 μM
孵育时间 4天
方法

细胞以(3-4)×103细胞/孔的密度与AT-406接种在96孔平底细胞培养板,并培育4天。不同浓度AT-406处理后的细胞生长抑制率通过(2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺苯基)-2H-四唑谷氨酸盐 (WST-8)分析测定。将WST-8加入每孔,终浓度为10%,然后板在37 °C下培育2-3小时。样品吸光度在450 nm下使用TECAN ULTRA阅读器测量。抑制50%细胞生长的AT-406浓度(IC50)通过比较未处理细胞和AT-406处理细胞的吸光度计算。

实验图片 检测方法 检测指标 实验图片 PMID
Western blot cIAP-1 / XIAP / Mcl-1 / pS6K1 / Cleaved PARP 28036295
Growth inhibition assay Cell viability 28036295
体内研究(In Vivo)
体内研究活性 AT-406在小鼠,大鼠,非灵长类动物,和狗体内具有良好的药代动力学(PK)性能和口服生物利用度。在MDA-MB-231异种移植物中,AT-406有效诱导肿瘤组织中cIAP1降解和半胱天冬酶-8的加工,以及PARP的裂解,在100 mg/kg,甚至200 mg/kg剂量下具有良好的耐受性。AT-406诱导显著的肿瘤生长抑制,100 mg/kg下P为0.0012。[1]
动物实验 Animal Models 负荷MDA-MB-231 异种移植瘤的严重联合免疫缺陷(SCID)小鼠
Dosages 10 mg/kg (i.v.),10 mg/kg (p.o.),30 mg/kg (p.o.) 和 100 mg/kg (p.o.)
Administration 静脉注射(i.v.) 或 口服(p.o.)给药
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01265199 Terminated
Acute Myelogenous Leukemia (AML)
Ascenta Therapeutics|The Leukemia and Lymphoma Society
February 2011 Phase 1
NCT01078649 Completed
Cancer|Solid Tumors|Lymphoma|Malignancy
Debiopharm International SA
March 29 2010 Phase 1

化学信息&溶解度

分子量 561.71 分子式

C32H43N5O4

CAS号 1071992-99-8 SDF Download Xevinapant (AT406) SDF
Smiles CC(C)CC(=O)N1CCC2CCC(N2C(=O)C(C1)NC(=O)C(C)NC)C(=O)NC(C3=CC=CC=C3)C4=CC=CC=C4
储存条件(自收到货起)

体外溶解度
批次:

DMSO : 112 mg/mL ( 199.39 mM; DMSO吸湿会降低化合物溶解度,请使用新开封DMSO)

Ethanol : 112 mg/mL

Water : 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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