Fexagratinib (AZD4547)
别名: ABSK 091
Fexagratinib (AZD4547,ABSK 091)是一种新型选择性的FGFR抑制剂，靶向作用于FGFR1/2/3，在无细胞试验中IC50为0.2 nM/2.5 nM/1.8 nM，对FGFR4， VEGFR2(KDR)具有微弱的作用活性，对IGFR， CDK2和p38几乎没有作用活性。Phase 2/3。
Fexagratinib (AZD4547) Chemical Structure
CAS: 1035270-39-3
产品质控
批次：
纯度：
99.94%
99.94
Fexagratinib (AZD4547) 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 |
|---|---|---|---|---|---|
| SK-HEP-1 | Function Assay | 0-2 μM | 48 h | causes a decrease of FRS2，AKT, and ERK phosphorylation | 26351320 |
| SNU449 | Function Assay | 0-2 μM | 48 h | causes a decrease of FRS2，AKT, and ERK phosphorylation | 26351320 |
| SK-HEP-1 | Clonogenic assay | 1 µM | 24 h | decreases colony formation significantly | 26351320 |
| SNU449 | Clonogenic assay | 1 µM | 24 h | decreases colony formation significantly | 26351320 |
| A549 | Cell viability Assay | 0.1/1 μM | 48 h | enhances Erlotinib induced viability loss | 26053020 |
| SGC-7901 | Growth Inhibition Assay | 1 nM-10 μM | 72 h | IC50 of 5-10 μM, inhibits cell viability dose dependently | 25576915 |
| HGC-27 | Growth Inhibition Assay | 1 nM-10 μM | 72 h | IC50 of 5-10 μM, inhibits cell viability dose dependently | 25576915 |
| MKN-28 | Growth Inhibition Assay | 1 nM-10 μM | 72 h | IC50 of 5-10 μM, inhibits cell viability dose dependently | 25576915 |
| NCI-N87 | Growth Inhibition Assay | 1 nM-10 μM | 72 h | IC50 of 5-10 μM, inhibits cell viability dose dependently | 25576915 |
| KATOIII | Growth Inhibition Assay | 1 nM-10 μM | 72 h | IC50 of 10-100 nM, inhibits cell viability dose dependently | 25576915 |
| SNU-16 | Growth Inhibition Assay | 1 nM-10 μM | 72 h | IC50 of 10-100 nM, inhibits cell viability dose dependently | 25576915 |
| 4T1 | Apoptosis Assay | 1.25-20 μM | 24 h | induces apoptosis dose dependently | 24642893 |
| HepG2 | Growth Inhibition Assay | 72 h | IC50=8.73 μM | 26351320 | |
| Hur7 | Growth Inhibition Assay | 72 h | IC50=7.25 μM | 26351320 | |
| PLC/PRF5 | Growth Inhibition Assay | 72 h | IC50=6.55 μM | 26351320 | |
| Hep3B | Growth Inhibition Assay | 72 h | IC50=6.43 μM | 26351320 | |
| SNU475 | Growth Inhibition Assay | 72 h | IC50=5.4 μM | 26351320 | |
| SK-HEP-1 | Growth Inhibition Assay | 72 h | IC50=0.084 μM | 26351320 | |
| SNU449 | Growth Inhibition Assay | 72 h | IC50=0.082 μM | 26351320 | |
| KG1 | Function assay | 72 hrs | Inhibition of FGFR1 in human KG1 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0002 μM. | 27117427 | |
| RT112 | Function assay | 72 hrs | Inhibition of FGFR3 in human RT112 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0006 μM. | 27117427 | |
| KG1 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human KG1 cells expressing FGFR1 after 72 hrs, IC50 = 0.0019 μM. | 29775937 | |
| KG1 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human KG1 cells after 72 hrs by CCK-8 assay, IC50 = 0.0033 μM. | 28687204 | |
| SNU16 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human SNU16 cells after 72 hrs by CCK-8 assay, IC50 = 0.0034 μM. | 28687204 | |
| SNU16 | Function assay | 72 hrs | Inhibition of recombinant FGFR2 in human SNU16 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0036 μM. | 27117427 | |
| SNU16 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human SNU16 cells expressing FGFR2 after 72 hrs, IC50 = 0.0062 μM. | 29775937 | |
| KG1 | Antiproliferative assay | 72 hrs | Antiproliferative activity against FGFR1-translocated human KG1 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0064 μM. | 27348537 | |
| SNU16 | Antiproliferative assay | 72 hrs | Antiproliferative activity against FGFR2-amplified human SNU16 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0134 μM. | 27348537 | |
| KATO III | Function assay | 72 hrs | Inhibition of FGFR2 in human KATO III cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0141 μM. | 28714692 | |
| KG1 | Function assay | 72 hrs | Inhibition of FGFR1OP2 fused FGFR1 in human KG1 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0161 μM. | 28714692 | |
| KATO III | Function assay | 72 hrs | Inhibition of FGFR2 in human KATO III cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0202 μM. | 27117427 | |
| SNU16 | Function assay | 72 hrs | Inhibition of FGFR2 in human SNU16 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0254 μM. | 28714692 | |
| UM-UC-14 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human UM-UC-14 cells expressing FGFR3 after 72 hrs, IC50 = 0.0269 μM. | 29775937 | |
| RT112 | Function assay | 72 hrs | Inhibition of FGFR3 in human RT112 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.027 μM. | 28714692 | |
| UM-UC-14 | Function assay | 72 hrs | Inhibition of FGFR3 mutant in human UM-UC-14 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0271 μM. | 28714692 | |
| RT112 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human RT112 cells after 72 hrs by MTT assay, GI50 = 0.0292 μM. | 27599742 | |
| H1581 | Function assay | 72 hrs | Inhibition of FGFR1 in human H1581 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0329 μM. | 27117427 | |
| NCI-H1581 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human NCI-H1581 cells expressing FGFR1 after 72 hrs, IC50 = 0.04 μM. | 29775937 | |
| B16F10 | Cytotoxicity assay | 72 hrs | Cytotoxicity against mouse B16F10 cells after 72 hrs by MTT assay, IC50 = 0.051 μM. | 25736993 | |
| A549 | Cytotoxicity assay | 72 hrs | Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.062 μM. | 25736993 | |
| NCI-H1581 | Function assay | 72 hrs | Inhibition of FGFR1 in human NCI-H1581 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0626 μM. | 28714692 | |
| RT112 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human RT112 cells expressing FGFR3 after 72 hrs, IC50 = 0.0838 μM. | 29775937 | |
| RT112 | Antiproliferative assay | 72 hrs | Antiproliferative activity against FGFR3-amplified human RT112 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0884 μM. | 27348537 | |
| NCI-H1581 | Antiproliferative assay | 72 hrs | Antiproliferative activity against FGFR1-amplified human NCI-H1581 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0921 μM. | 27348537 | |
| HeLa 229 | Cytotoxicity assay | 72 hrs | Cytotoxicity against human HeLa 229 cells after 72 hrs by MTT assay, IC50 = 0.14 μM. | 25736993 | |
| BAF3 | Antiproliferative assay | 72 hrs | Antiproliferative activity against mouse BAF3 cells expressing VEGFR2 after 72 hrs, IC50 = 0.222 μM. | 29775937 | |
| SGC7901 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human SGC7901 cells after 72 hrs by MTT assay, IC50 = 2.8 μM. | 27829519 | |
| MGC803 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MGC803 cells after 72 hrs by MTT assay, IC50 = 6.2 μM. | 27829519 | |
| BGC823 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human BGC823 cells after 72 hrs by MTT assay, IC50 = 7.9 μM. | 27829519 | |
| HL7702 | Cytotoxicity assay | 72 hrs | Cytotoxicity against human HL7702 cells after 72 hrs by MTT assay, IC50 = 18.21 μM. | 25736993 | |
| HEC1A Normal FGFR2 | Growth Inhibition Assay | GI50﹥10 μM | 26294741 | ||
| Ishikawa FGFF2 over exp. | Growth Inhibition Assay | GI50=4.5 ± 1.51 μM | 26294741 | ||
| MFE280 FGFR2 S252W | Growth Inhibition Assay | GI50=0.218 ± 0.073 μM | 26294741 | ||
| MFE296 FGFR2 N550K | Growth Inhibition Assay | GI50=0.730 ± 0.057 μM | 26294741 | ||
| AN3-CA FGFR2 N550K, K310R | Growth Inhibition Assay | GI50=0.031 ± 0.023 μM | 26294741 | ||
| TT RET C634W | Growth Inhibition Assay | GI50=2.9 ± 0.904 μM | 26294741 | ||
| MV4-11 FLT3/ITD | Growth Inhibition Assay | GI50=0.459 ± 0.046 μM | 26294741 | ||
| MOLM14 FLT3/ITD | Growth Inhibition Assay | GI50=0.484 ± 0.157 μM | 26294741 | ||
| BaF3 Parental | Growth Inhibition Assay | GI50﹥10 μM | 26294741 | ||
| BaF3 RET-TEL | Growth Inhibition Assay | GI50=0.39 ± 0.048 μM | 26294741 | ||
| BaF3 FLT3-TEL | Growth Inhibition Assay | GI50=4.6 ± 0.577 μM | 26294741 | ||
| 4T1 | Growth Inhibition Assay | IC50=0.64±0.11 μM | 24642893 | ||
| MDA-MB-468 | Growth Inhibition Assay | IC50=4.9±0.85 μM | 24642893 | ||
| HCT116 | Growth Inhibition Assay | IC50=15.9±1.82 μM | 24642893 | ||
| SW620 | Growth Inhibition Assay | IC50＞20 μM | 24642893 | ||
| MDA-MB-231 | Growth Inhibition Assay | IC50＞20 μM | 24642893 | ||
| CT26 | Growth Inhibition Assay | IC50＞20 μM | 24642893 | ||
| SW480 | Growth Inhibition Assay | IC50＞20 μM | 24642893 | ||
| KG1a | Growth Inhibition Assay | IC50=0.018 μM | 22369928 | ||
| Sum52-PE | Growth Inhibition Assay | IC50=0.041 μM | 22369928 | ||
| KMS11 | Growth Inhibition Assay | IC50=0.281 μM | 22369928 | ||
| MCF7 | Growth Inhibition Assay | IC50>30 μM | 22369928 | ||
| U-2 OS | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells | 29435139 | ||
| A673 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | ||
| Saos-2 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells | 29435139 | ||
| BT-37 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells | 29435139 | ||
| RD | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells | 29435139 | ||
| SK-N-SH | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells | 29435139 | ||
| BT-12 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells | 29435139 | ||
| OHS-50 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells | 29435139 | ||
| fibroblast cells | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for control Hh wild type fibroblast cells | 29435139 | ||
| Rh41 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells | 29435139 | ||
| Rh30 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh30 cells | 29435139 | ||
| SJ-GBM2 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells | 29435139 | ||
| NB-EBc1 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells | 29435139 | ||
| LAN-5 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells | 29435139 | ||
| Rh18 | qHTS ssay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells | 29435139 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Fexagratinib (AZD4547,ABSK 091)是一种新型选择性的FGFR抑制剂，靶向作用于FGFR1/2/3，在无细胞试验中IC50为0.2 nM/2.5 nM/1.8 nM，对FGFR4， VEGFR2(KDR)具有微弱的作用活性，对IGFR， CDK2和p38几乎没有作用活性。Phase 2/3。 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 特性 | AZD4547高选择性作用于 FGFR1-3，比作用于FGFR4选择性高。AZD4547有效作用于野生型和突变型FGFR酪氨酸激酶活性。 | ||||||||
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | 与 FGFR1-3相比, AZD4547作用于FGFR4，活性微弱，IC50为165 nM。AZD4547 只抑制重组 VEGFR2 (KDR) 激酶活性， IC50为 24 nM,在体外选择性作用于一组多种代表性的人类激酶。0.1 μM AZD4547 作用于一系列重组激酶，包括 ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2,和 PI3K，没有作用活性。相应地,在细胞磷酸化实验中，可观察到AZD4547 作用于FGFR1-3的选择性比作用于 FGFR4, IGFR, 和 KDR高。AZD4547在体外,只有作用于表达去调控FGFRs 如KG1a, Sum52-PE,和KMS11的肿瘤细胞，具有有效抗增殖活性，IC50 为18-281 nM,而对MCF7 及100 种以上其他肿瘤细胞无活性。AZD4547 处理人类肿瘤细胞，有效抑制FGFR 和 MAPK 磷酸化,这种作用存在剂量依赖性。AZD4547 也有效抑制FRS2 和 PLCγ磷酸化,及下游FGFR信号。另外, AZD4547作用于乳腺细胞系，MCF7和Sum52-PE 而不是KG1a和 KMS11细胞，影响AKT磷酸化。AZD4547处理Sum52-PE 和 KMS11细胞，显著诱导凋亡,作用于KG1a细胞，显著提高细胞周期在G1期停滞而不是凋亡, 而作用于MCF7细胞，对细胞周期分布和凋亡都没有作用效果。[1] |
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|---|---|---|---|---|
| 激酶实验 | AZD4547 激酶活性 | |||
| 使用浓度等于或低于相对Km 的ATP，测定AZD4547抑制 FGFR1-3的人类重组激酶活性的效果。 | ||||
| 细胞实验 | 细胞系 | KG1a, Sum52-PE, KMS11, 和MCF7 | ||
| 浓度 | 溶于DMSO,终浓度为 ~1 μM | |||
| 孵育时间 | 72 小时 | |||
| 方法 | 使用多种浓度AZD4547处理细胞72小时。通过 MTS 增殖实验获得抗增殖的IC50值。荧光激活细胞分选(FACS)中,细胞与70%乙醇混合，然后与碘化丙啶/RNase A标记溶液温育。使用 FACSCalibur 仪器和CellQuest分析软件测定细胞周期谱。为了分析凋亡，轻轻收集细胞和培养基，离心，然后冲洗细胞颗粒。细胞进行Annexin膜联蛋白 V-异硫氰酸荧光素(FITC)染色和碘化丙啶吸收。使用FACSCalibur仪器测定 膜联蛋白 V染色阳性细胞比例，使用CellQuest分析软件进行象限分类。 |
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| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | p-FGFR / FGFR1 / p-AKT / AKT / p-ERK / ERK pFRS2 |
|
28900173 | |
| Growth inhibition assay | Cell viability Cell viability |
|
28900173 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | AZD4547按3 mg/kg剂量口服处理携带KMS11肿瘤的小鼠，每天两次，与空白对照组相比，显著抑制53%肿瘤生长，AZD4547 按 12.5 mg/kg剂量每天处理一次，或按 6.25 mg/kg剂量每天处理两次，则完全抑制肿瘤，这与p-FGFR3的药效学调节剂量正相关，且降低 KMS11肿瘤细胞增殖。而且, AZD4547按 12.5 mg/kg剂量口服处理给药FGFR1融合KG1a 移植瘤模型，每天一次，抑制65% 肿瘤生长。在有效剂量水平，AZD4547不表现出抗血管生成的效果。AZD4547 对血压没有显著作用效果，因此在体内缺乏 抗-KDR 活性。相应地, AZD4547按6.25 mg/kg剂量口服处理对Cediranib敏感的移植瘤模型，包括 Calu-6, HCT-15 和 LoVo，每天两次，没有作用活性。[1] |
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|---|---|---|
| 动物实验 | Animal Models | 皮下注射LoVo, HCT-15, Calu-6, KMS11 或 KG1a的雌性Swiss衍生裸鼠和SCID小鼠 |
| Dosages | 1.5-50 mg/kg | |
| Administration | 口服饲喂，每天一次或两次 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT02824133 | Completed | Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion|Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion |
Assistance Publique - Hôpitaux de Paris |
September 2015 | Phase 1|Phase 2 |
| NCT01824901 | Completed | Recurrent Non-small Cell Lung Cancer|Squamous Cell Lung Cancer |
ECOG-ACRIN Cancer Research Group|National Cancer Institute (NCI)|Eastern Cooperative Oncology Group |
January 15 2014 | Phase 1|Phase 2 |
| NCT01795768 | Unknown status | Gastric Cancer|Oesophageal Cancer|Breast Cancer|Squamous Cell Carcinoma of the Lung |
Royal Marsden NHS Foundation Trust|AstraZeneca |
September 2012 | Phase 2 |
| NCT01213160 | Completed | Cancer|Advanced Solid Malignancies |
AstraZeneca |
November 2010 | Phase 1 |
化学信息&溶解度
| 分子量 | 463.57 | 分子式 | C26H33N5O3 |
| CAS号 | 1035270-39-3 | SDF | Download Fexagratinib (AZD4547) SDF |
| Smiles | CC1CN(CC(N1)C)C2=CC=C(C=C2)C(=O)NC3=NNC(=C3)CCC4=CC(=CC(=C4)OC)OC | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 93 mg/mL ( (200.61 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 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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