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Fexagratinib (AZD4547)
別名: ABSK 091
Fexagratinib (AZD4547,ABSK 091)是一種新型選擇性的FGFR抑制劑，靶向作用于FGFR1/2/3，在無細胞試驗中IC50為0.2 nM/2.5 nM/1.8 nM，對FGFR4， VEGFR2(KDR)具有微弱的作用活性，對IGFR， CDK2和p38幾乎沒有作用活性。Phase 2/3。
Fexagratinib (AZD4547) Chemical Structure
CAS: 1035270-39-3
產(chǎn)品質(zhì)控
批次：
純度：
99.94%
99.94
Fexagratinib (AZD4547) 相關(guān)產(chǎn)品
| 相關(guān)靶點 | FGFR1 FGFR2 FGFR3 FGFR4 | 點擊展開 |
|---|---|---|
| 相關(guān)產(chǎn)品 | PD173074 BLU9931 LY2874455 Zoligratinib (Debio-1347) Futibatinib (TAS-120) PD-166866 SSR128129E H3B-6527 Fisogatinib (BLU-554) Derazantinib FIIN-2 Ferulic Acid ASP5878 Roblitinib (FGF401) Alofanib (RPT835) NSC12 PRN1371 | 點擊展開 |
| 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 | 點擊展開 |
相關(guān)信號通路圖
細胞實驗數(shù)據(jù)示例
| 細胞系 | 實驗類型 | 給藥濃度 | 孵育時間 | 活性描述 | 文獻信息 |
|---|---|---|---|---|---|
| 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 | ||
| 點擊查看更多細胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | Fexagratinib (AZD4547,ABSK 091)是一種新型選擇性的FGFR抑制劑，靶向作用于FGFR1/2/3，在無細胞試驗中IC50為0.2 nM/2.5 nM/1.8 nM，對FGFR4， VEGFR2(KDR)具有微弱的作用活性，對IGFR， CDK2和p38幾乎沒有作用活性。Phase 2/3。 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 特性 | AZD4547高選擇性作用于 FGFR1-3，比作用于FGFR4選擇性高。AZD4547有效作用于野生型和突變型FGFR酪氨酸激酶活性。 | ||||||||
| 靶點 |
|
| 體外研究(In Vitro) | ||||
| 體外研究活性 | 與 FGFR1-3相比, AZD4547作用于FGFR4，活性微弱，IC50為165 nM。AZD4547 只抑制重組 VEGFR2 (KDR) 激酶活性， IC50為 24 nM,在體外選擇性作用于一組多種代表性的人類激酶。0.1 μM AZD4547 作用于一系列重組激酶，包括 ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2,和 PI3K，沒有作用活性。相應(yīng)地,在細胞磷酸化實驗中，可觀察到AZD4547 作用于FGFR1-3的選擇性比作用于 FGFR4, IGFR, 和 KDR高。AZD4547在體外,只有作用于表達去調(diào)控FGFRs 如KG1a, Sum52-PE,和KMS11的腫瘤細胞，具有有效抗增殖活性，IC50 為18-281 nM,而對MCF7 及100 種以上其他腫瘤細胞無活性。AZD4547 處理人類腫瘤細胞，有效抑制FGFR 和 MAPK 磷酸化,這種作用存在劑量依賴性。AZD4547 也有效抑制FRS2 和 PLCγ磷酸化,及下游FGFR信號。另外, AZD4547作用于乳腺細胞系，MCF7和Sum52-PE 而不是KG1a和 KMS11細胞，影響AKT磷酸化。AZD4547處理Sum52-PE 和 KMS11細胞，顯著誘導(dǎo)凋亡,作用于KG1a細胞，顯著提高細胞周期在G1期停滯而不是凋亡, 而作用于MCF7細胞，對細胞周期分布和凋亡都沒有作用效果。[1] |
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|---|---|---|---|---|
| 激酶實驗 | AZD4547 激酶活性 | |||
| 使用濃度等于或低于相對Km 的ATP，測定AZD4547抑制 FGFR1-3的人類重組激酶活性的效果。 | ||||
| 細胞實驗 | 細胞系 | KG1a, Sum52-PE, KMS11, 和MCF7 | ||
| 濃度 | 溶于DMSO,終濃度為 ~1 μM | |||
| 孵育時間 | 72 小時 | |||
| 方法 | 使用多種濃度AZD4547處理細胞72小時。通過 MTS 增殖實驗獲得抗增殖的IC50值。熒光激活細胞分選(FACS)中,細胞與70%乙醇混合，然后與碘化丙啶/RNase A標(biāo)記溶液溫育。使用 FACSCalibur 儀器和CellQuest分析軟件測定細胞周期譜。為了分析凋亡，輕輕收集細胞和培養(yǎng)基，離心，然后沖洗細胞顆粒。細胞進行Annexin膜聯(lián)蛋白 V-異硫氰酸熒光素(FITC)染色和碘化丙啶吸收。使用FACSCalibur儀器測定 膜聯(lián)蛋白 V染色陽性細胞比例，使用CellQuest分析軟件進行象限分類。 |
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| 實驗圖片 | 檢測方法 | 檢測指標(biāo) | 實驗圖片 | PMID |
| Western blot | p-FGFR / FGFR1 / p-AKT / AKT / p-ERK / ERK pFRS2 |
|
28900173 | |
| Growth inhibition assay | Cell viability Cell viability |
|
28900173 | |
| 體內(nèi)研究(In Vivo) | ||
| 體內(nèi)研究活性 | AZD4547按3 mg/kg劑量口服處理攜帶KMS11腫瘤的小鼠，每天兩次，與空白對照組相比，顯著抑制53%腫瘤生長，AZD4547 按 12.5 mg/kg劑量每天處理一次，或按 6.25 mg/kg劑量每天處理兩次，則完全抑制腫瘤，這與p-FGFR3的藥效學(xué)調(diào)節(jié)劑量正相關(guān)，且降低 KMS11腫瘤細胞增殖。而且, AZD4547按 12.5 mg/kg劑量口服處理給藥FGFR1融合KG1a 移植瘤模型，每天一次，抑制65% 腫瘤生長。在有效劑量水平，AZD4547不表現(xiàn)出抗血管生成的效果。AZD4547 對血壓沒有顯著作用效果，因此在體內(nèi)缺乏 抗-KDR 活性。相應(yīng)地, AZD4547按6.25 mg/kg劑量口服處理對Cediranib敏感的移植瘤模型，包括 Calu-6, HCT-15 和 LoVo，每天兩次，沒有作用活性。[1] |
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|---|---|---|
| 動物實驗 | 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 | 口服飼喂，每天一次或兩次 | |
| 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 - H?pitaux 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 |
化學(xué)信息&溶解度
| 分子量 | 463.57 | 分子式 | C26H33N5O3 |
| CAS號 | 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 | ||
| 儲存條件(自收到貨起) | |||
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體外溶解度 |
DMSO : 93 mg/mL ( (200.61 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Water : Insoluble Ethanol : Insoluble |
摩爾濃度計算器 |
|
體內(nèi)溶解度 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)配方計算器 | ||||
實驗計算
動物體內(nèi)配方計算器（澄清溶液）
第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）
mg/kg
g
μL
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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