Agerafenib (CEP-32496)

别名: RXDX-105

Agerafenib (CEP-32496) 是一种高度有效的BRAF(V600E/WT)c-Raf抑制剂,Kd为14 nM/36 nM和39 nM,适度有效作用于Abl-1, c-Kit, RET (c-RET), PDGFRβ和VEGFR2,对MEK-1, MEK-2, ERK-1和ERK-2具有微弱的亲和力。Phase 1/2。

Agerafenib (CEP-32496) Chemical Structure

Agerafenib (CEP-32496) Chemical Structure

CAS: 1188910-76-0

规格 价格 库存 购买数量
10mM (1mL in DMSO) 2990 现货
5mg 2200.97 现货
200mg 16298.1 现货
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产品质控

批次: S801501 DMSO]9 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false 纯度: 99.19%
99.19

Agerafenib (CEP-32496)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
COLO205 Antitumor assay 10 mg/kg 14 days Antitumor activity against human COLO205 cells xenografted in athymic nude mouse at 10 mg/kg, po bid for 14 days 22168626
COLO205 Antitumor assay 30 mg/kg 14 days Antitumor activity against human COLO205 cells xenografted in athymic nude mouse at 30 mg/kg, po bid for 14 days 22168626
COLO205 Antitumor assay 100 mg/kg 14 days Antitumor activity against human COLO205 cells xenografted in athymic nude mouse at 100 mg/kg, po bid for 14 days 22168626
HEK293 Function assay 1 hr Inhibition of LCK in human HEK293 cells after 1 hr by competition binding assay, Kd=0.002μM. 22168626
HEK293 Function assay 1 hr Inhibition of PDGFRbeta in human HEK293 cells after 1 hr by competition binding assay, Kd=0.002μM. 22168626
HEK293 Function assay 1 hr Inhibition of cKit in human HEK293 cells after 1 hr by competition binding assay, Kd=0.002μM. 22168626
HEK293 Function assay 1 hr Inhibition of Ret in human HEK293 cells after 1 hr by competition binding assay, Kd=0.002μM. 22168626
HEK293 Function assay 1 hr Inhibition of Abl1 in human HEK293 cells after 1 hr by competition binding assay, Kd=0.003μM. 22168626
HEK293 Function assay 1 hr Inhibition of VEGFR2 in human HEK293 cells after 1 hr by competition binding assay, Kd=0.008μM. 22168626
HEK293 Function assay 1 hr Inhibition of CSF1R in human HEK293 cells after 1 hr by competition binding assay, Kd=0.009μM. 22168626
HEK293 Function assay 1 hr Inhibition of EPHA2 in human HEK293 cells after 1 hr by competition binding assay, Kd=0.014μM. 22168626
HEK293 Function assay 1 hr Inhibition of BRAF V600E mutant in human HEK293 cells after 1 hr by competition binding assay, Kd=0.014μM. 22168626
HEK293 Function assay 1 hr Inhibition of EGFR in human HEK293 cells after 1 hr by competition binding assay, Kd=0.022μM. 22168626
HEK293 Function assay 1 hr Inhibition of wild type BRAF in human HEK293 cells after 1 hr by competition binding assay, Kd=0.036μM. 22168626
COLO205 Cytotoxicity assay 72 hrs Cytotoxicity against human COLO205 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, EC50=0.036μM. 22168626
HEK293 Function assay 1 hr Inhibition of CRAF in human HEK293 cells after 1 hr by competition binding assay, Kd=0.039μM. 22168626
A375 Cytotoxicity assay 72 hrs Cytotoxicity against human A375 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, IC50=0.078μM. 22168626
A375 Function assay 2 hrs Inhibition of BRAF V600E mutant-mediated MEK phosphorylation in human A375 cells after 2 hrs, IC50=0.082μM. 22168626
COLO679 Cytotoxicity assay 72 hrs Cytotoxicity against human COLO679 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, EC50=0.211μM. 22168626
HT144 Cytotoxicity assay 72 hrs Cytotoxicity against human HT144 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, EC50=0.228μM. 22168626
SK-MEL-28 Cytotoxicity assay 72 hrs Cytotoxicity against human SK-MEL-28 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, EC50=0.454μM. 22168626
HEK293 Function assay 1 hr Inhibition of cMET in human HEK293 cells after 1 hr by competition binding assay, Kd=0.513μM. 22168626
HCT116 Cytotoxicity assay 72 hrs Cytotoxicity against human HCT116 cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=0.669μM. 22168626
Hs578T Cytotoxicity assay 72 hrs Cytotoxicity against human Hs578T cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=2.736μM. 22168626
DU145 Cytotoxicity assay 72 hrs Cytotoxicity against human DU145 cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=2.911μM. 22168626
HEK293 Function assay 1 hr Inhibition of JAK2 in human HEK293 cells after 1 hr by competition binding assay, Kd=4.7μM. 22168626
PC3 Cytotoxicity assay 72 hrs Cytotoxicity against human PC3 cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=6.257μM. 22168626
LNCAP Cytotoxicity assay 72 hrs Cytotoxicity against human LNCAP cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=6.631μM. 22168626
HEK293 Function assay 1 hr Inhibition of MEK1 in human HEK293 cells after 1 hr by competition binding assay, Kd=7.1μM. 22168626
HEK293 Function assay 1 hr Inhibition of MEK2 in human HEK293 cells after 1 hr by competition binding assay, Kd=8.3μM. 22168626
HCC827 Function assay Displacement of [3H]-cyclopamine from SMO V404M mutant in gefitinib resistant human HCC827 cells by scintillation counting, Ki=0.1878μM. 28787156
点击查看更多细胞系数据

生物活性

产品描述 Agerafenib (CEP-32496) 是一种高度有效的BRAF(V600E/WT)c-Raf抑制剂,Kd为14 nM/36 nM和39 nM,适度有效作用于Abl-1, c-Kit, RET (c-RET), PDGFRβ和VEGFR2,对MEK-1, MEK-2, ERK-1和ERK-2具有微弱的亲和力。Phase 1/2。
特性 对BRAF(V600E)突变型和相关的c-Raf具有高的结合亲和力,而对MAPK通路的其它关键激酶,包括MEK-1,MEK-2,ERK-1和ERK-2无显著的亲和力。
靶点
c-Kit [1] LCK [1] PDGFRβ [1] RET [1] Abl1 [1] 点击更多
2 nM(Kd) 2 nM(Kd) 2 nM(Kd) 2 nM(Kd) 3 nM(Kd)
体外研究(In Vitro)
体外研究活性 CEP-32496抑制A375细胞(BRAFV600E) 增殖, EC50为78 nM。CEP-32496作用于肿瘤细胞系,对表达突变型BRAF的A375, SK-MEL-28, Colo-205, Colo-679, 和HT-144细胞比表达野生型BRAF的HCT116, Hs578T, LNCaP, DU145, 和PC-3细胞具有更敏感的细胞毒性作用。[1]CEP-32496作用于人类黑色素瘤(A375)和结肠直肠癌(Colo-205)细胞系,抑制MAPK/MEK磷酸化,IC50分别为 78 nM 和 60 nM。[2]
激酶实验 结合实验
结合反应在室温下进行1小时,通过捕获固定化的亲和配体,测定未与实验化合物结合的激酶组分,通过定量PCR检测进行定量分析。分别测定CEP-32496作用于每种激酶的效果。使用11种连续3倍稀释液测定Kd值,并表示为实验按一式两份进行的平均值。各个值之间的变异性小于2倍。
细胞实验 细胞系 A375 细胞系
浓度 78 nM
孵育时间 72 小时
方法 细胞按每孔104个细胞接种在含10%胎牛血清的DMEM培养基中进行培养。使用PBS洗涤细胞,更换为含0.5%血清的DMEM培养基,温育过夜。加入不同浓度CEP-32496,DMSO 终浓度为0.5%,温育72小时。温育末期,加入Cell Titer Blue,再温育3小时。使用SoftMax Pro (激发波长为560 nm,发射波长为590 nm) 测量荧光信号的强度,对剩余的存活细胞进行定量。使用含有Igor Pro 的9点曲线推算IC50值,并且表示为实验按一式两份进行的平均值。各个值之间的变异性小于2倍。
实验图片 检测方法 检测指标 实验图片 PMID
Growth inhibition assay Cell viability 31695841
Western blot p-RET / RET / p-PLCγ / PLCγ / p-ERK / ERK / p-MEK / MEK 28011461
体内研究(In Vivo)
体内研究活性 CEP-32496处理小鼠,狗,猴和人肝微粒制品,具有良好的稳定性,测量的内在清除率为<23 (μL/min)/mg,t1/2为>60 分钟。CEP-32496按30 mg/kg剂量口服处理给药携带Colo-205移植瘤的小鼠模型,每天两次,肿瘤生长停滞,部分肿瘤消退(PRs)的发生率为40%,而按100 mg/kg剂量处理,则肿瘤生长停滞,部分肿瘤消退(PRs)的发生率为80%。CEP-32496按30 mg/kg剂量口服处理肿瘤裂解物,每天两次,在给药时间点厚2小时和6小时,分别抑制50%和75%归一化的pMEK,而按55 mg/kg剂量处理给药携带Colo-205移植瘤的小鼠模型, 抑制57%到75%pMEK。[1]CEP-32496处理多个临床前物种具有良好的口服生物利用度(大鼠,狗和猴> 95%)。CEP-32496(100 mg/kg)处理携带BRAF(V600E)结肠癌移植瘤的裸鼠,抑制pMEK和pERK,使肿瘤持续生长停滞和衰退。[2]
动物实验 Animal Models 携带Colo-205移植瘤的小鼠模型
Dosages 100 mg/kg
Administration 口服饲喂

化学信息&溶解度

分子量 517.46 分子式

C24H22F3N5O5

CAS号 1188910-76-0 SDF Download Agerafenib (CEP-32496) SDF
Smiles CC(C)(C1=CC(=NO1)NC(=O)NC2=CC(=CC=C2)OC3=NC=NC4=CC(=C(C=C43)OC)OC)C(F)(F)F
储存条件(自收到货起)

体外溶解度
批次:

DMSO : 9 mg/mL ( (17.39 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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