Fedratinib (TG101348)
别名: SAR302503 中文名称：费德拉替尼
Fedratinib (SAR302503, TG101348)是一种选择性JAK2抑制剂，在无细胞试验中IC50为3 nM，作用于JAK2比作用于JAK1和JAK3选择性高35和334倍。Fedratinib也可抑制 FMS-like tyrosine kinase 3 (FLT3) 和 Ret (c-RET)，对应的IC50值分别为15 nM和48 nM。Fedratinib有潜在的抗肿瘤活性。Fedratinib可抑制细胞增殖并促进凋亡。Phase 2。
Fedratinib (TG101348) Chemical Structure
CAS: 936091-26-8
产品质控
批次：
纯度：
99.99%
99.99
常与Fedratinib (TG101348)一起在实验中被使用的化合物
对于Ruxolitinib失败的患者来说，Fedratinib是治疗骨髓纤维化的更好选择。
Fedratinib和Vincristine联合治疗可降低KBV20C细胞的细胞活力、增加G2期阻滞并上调细胞凋亡。
Fedratinib和Venetoclax联合治疗可降低RS4;11和SUPB-15细胞中FLT3+B-ALL的存活和增殖。
Fedratinib和Pacritinib是FDA批准的JAK2抑制剂，用于hydroxyurea/ruxolitinib治疗失败/血小板计数<50×10(9)/L的患者。
Fedratinib和Momelotinib是正在测试的用于治疗骨髓增殖性肿瘤的新型JAK抑制剂。
Patel AA, et al. Curr Hematol Malig Rep. 2020 Dec;15(6):409-418.
Fedratinib (TG101348)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 |
|---|---|---|---|---|---|
| HDLM2 | Function Assay | 0-5 μM | 24 h | inhibits JAK2/STAT signaling | 24610827 |
| SUPHD1 | Function Assay | 0-5 μM | 24 h | inhibits JAK2/STAT signaling | 24610827 |
| L1236 | Function Assay | 0-5 μM | 24 h | inhibits JAK2/STAT signaling | 24610827 |
| KMH2 | Function Assay | 0-5 μM | 24 h | inhibits JAK2/STAT signaling | 24610827 |
| L428 | Function Assay | 0-5 μM | 24 h | inhibits JAK2/STAT signaling | 24610827 |
| K1106P | Apoptosis Assay | 0/0.625/1.25 μM | 48 h | induces the apoptosis | 24610827 |
| HDLM2 | Apoptosis Assay | 0/0.625/1.25 μM | 48 h | induces the apoptosis | 24610827 |
| SUPHD1 | Apoptosis Assay | 0/0.625/1.25 μM | 48 h | induces the apoptosis | 24610827 |
| L1236 | Apoptosis Assay | 0/0.625/1.25 μM | 48 h | induces the apoptosis | 24610827 |
| KMH2 | Apoptosis Assay | 0/0.625/1.25 μM | 48 h | induces the apoptosis | 24610827 |
| L428 | Apoptosis Assay | 0/0.625/1.25 μM | 48 h | induces the apoptosis | 24610827 |
| K1106P | Growth Inhibition Assay | 0-5 μM | 48 h | inhibits cell growth significantly | 24610827 |
| HDLM2 | Growth Inhibition Assay | 0-5 μM | 48 h | inhibits cell growth significantly | 24610827 |
| SUPHD1 | Growth Inhibition Assay | 0-5 μM | 48 h | inhibits cell growth significantly | 24610827 |
| L1236 | Growth Inhibition Assay | 0-5 μM | 48 h | inhibits cell growth significantly | 24610827 |
| KMH2 | Growth Inhibition Assay | 0-5 μM | 48 h | inhibits cell growth significantly | 24610827 |
| L428 | Growth Inhibition Assay | 0-5 μM | 48 h | inhibits cell growth significantly | 24610827 |
| MDA-MB-468 | Growth Inhibition Assay | 0-4 μM | 48 h | results significant loss of viability compared to RI-BPI alone | 24662818 |
| MDA-MB-468 | Growth Inhibition Assay | 3 µM | 48 h | enhanced sibcl6 induced loss of cell viability | 24662818 |
| K562 | Growth Inhibition Assay | 0-1 μM | 72 h | inhibits K562 cell proliferation at high concentration | 24775308 |
| K1106 | Function Assay | 1/2 μM | 24 h | decreases STAT6 phosphorylation concentration dependently | 24977668 |
| U2940 | Function Assay | 1/2 μM | 24 h | decreases STAT6 phosphorylation concentration dependently | 24977668 |
| MedB-1 | Function Assay | 1/2 μM | 24 h | decreases STAT6 phosphorylation concentration dependently | 24977668 |
| HEK293 MSR | Function Assay | 0-10 μM | 7 min | inhibits hTHTR2 with an IC50 of 1.2 µM | 25063672 |
| Caco-2 | Function Assay | 10/50/100 μM | 2 h | decreases the flux of [3H]thiamine across the monolayer with IC50 of 6.5 μM | 25063672 |
| Caco-2 | Function Assay | 0-120 μM | 7 min | inhibits thiamine uptake with an IC50 of 2.1 µM | 25063672 |
| CD4+ T | Function Assay | 0.01-1 μM | 48 h | reduces the phosphorylation levels of JAK2 and STAT3 | 25572535 |
| H1650 | Growth Inhibition Assay | 1 μM | 48 h | sensitizes cells to the cytotoxicity of erlotinib | 25869210 |
| H1975 | Growth Inhibition Assay | 1 μM | 48 h | sensitizes cells to the cytotoxicity of erlotinib | 25869210 |
| H1650 | Function Assay | 0.25-1 μM | 24 h | inhibits expression of apoptosis-related protein Bcl-XL, Bcl-2, survivin, XIAP | 25869210 |
| H1975 | Function Assay | 0.25-1 μM | 24 h | inhibits expression of apoptosis-related protein Bcl-XL, Bcl-2, survivin, XIAP | 25869210 |
| H1650 | Apoptosis Assay | 0.5-2 μM | 12-48 h | induces apoptosis in both dose- and time- dependent manner | 25869210 |
| H1975 | Apoptosis Assay | 0.5-2 μM | 12-48 h | induces apoptosis in both dose- and time- dependent manner | 25869210 |
| K1106P | Function Assay | 0-5 μM | 24 h | inhibits JAK2/STAT signaling | 24610827 |
| MedB-1 | Growth Inhibition Assay | 4 μM | 24/48/72 h | inhibits cell growth time dependently | 23852366 |
| K1106 | Growth Inhibition Assay | 4 μM | 24/48/72 h | inhibits cell growth time dependently | 23852366 |
| U2940 | Growth Inhibition Assay | 4 μM | 24/48/72 h | inhibits cell growth time dependently | 23852366 |
| M-MOK | Growth Inhibition Assay | 25 µM | 24/48/72 h | inhibits cell growth time dependently | 21853157 |
| FE-PD | Growth Inhibition Assay | 0.063-4 μM | IC50=9.5 μM, inhibits cell growth dose dependently | 23372669 | |
| HEL | Growth Inhibition Assay | 0.063-4 μM | IC50=1.5 μM, inhibits cell growth dose dependently | 23372669 | |
| K-562 | Growth Inhibition Assay | 0.063-4 μM | IC50=2.5 μM, inhibits cell growth dose dependently | 23372669 | |
| L-82 | Growth Inhibition Assay | 0.063-4 μM | IC50=0.98 μM, inhibits cell growth dose dependently | 23372669 | |
| MAC-1 | Growth Inhibition Assay | 0.063-4 μM | IC50=0.52 μM, inhibits cell growth dose dependently | 23372669 | |
| MAC-2A | Growth Inhibition Assay | 0.063-4 μM | IC50=0.69 μM, inhibits cell growth dose dependently | 23372669 | |
| MAC-2B | Growth Inhibition Assay | 0.063-4 μM | IC50=0.54 μM, inhibits cell growth dose dependently | 23372669 | |
| MY-LA | Growth Inhibition Assay | 0.063-4 μM | IC50=2.1 μM, inhibits cell growth dose dependently | 23372669 | |
| NC-NC | Growth Inhibition Assay | 0.063-4 μM | IC50=1.0 μM, inhibits cell growth dose dependently | 23372669 | |
| SE-AX | Growth Inhibition Assay | 0.063-4 μM | IC50=1.5 μM, inhibits cell growth dose dependently | 23372669 | |
| SR-786 | Growth Inhibition Assay | 0.063-4 μM | IC50=4.6 μM, inhibits cell growth dose dependently | 23372669 | |
| MV4-11 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MV4-11 cells after 72 hrs by celltiter-blue assay, EC50 = 0.079 μM. | 28280261 | |
| MM1S | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MM1S cells after 72 hrs by trypan blue exclusion assay, IC50 = 1 μM. | 28280261 | |
| MM.1S | Growth Inhibition Assay | IC50=1-3 μM | 24584101 | ||
| TpoR JAK2 WT | Growth Inhibition Assay | IC50=1.4 (1.3–1.5) μM | 24251790 | ||
| TpoR JAK2 V617F | Growth Inhibition Assay | IC50=0.8 (0.7–0.9) μM | 24251790 | ||
| TpoR W515L | Growth Inhibition Assay | IC50=0.8 (0.7–1.0) μM | 24251790 | ||
| Bcr-abl | Growth Inhibition Assay | IC50=2.7 (2.2–3.3) μM | 24251790 | ||
| JAK2 TW | Growth Inhibition Assay | IC50=1.8 (1.5–2.3) μM | 24251790 | ||
| JAK2 V617F | Growth Inhibition Assay | IC50=0.6 (0.6–0.7) μM | 24251790 | ||
| HEL | Growth Inhibition Assay | IC50=305 nM | 18394554 | ||
| Ba/F3 JAK2V617F | Growth Inhibition Assay | IC50=270 nM | 18394554 | ||
| NB1643 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 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 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Fedratinib (SAR302503, TG101348)是一种选择性JAK2抑制剂，在无细胞试验中IC50为3 nM，作用于JAK2比作用于JAK1和JAK3选择性高35和334倍。Fedratinib也可抑制 FMS-like tyrosine kinase 3 (FLT3) 和 Ret (c-RET)，对应的IC50值分别为15 nM和48 nM。Fedratinib有潜在的抗肿瘤活性。Fedratinib可抑制细胞增殖并促进凋亡。Phase 2。 | ||||||||
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| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | TG-101348也显著抑制JAK2 V617F, Flt3和Ret，IC50分别为3 nM, 15 nM和48 nM。TG101348对密切相关的JAK3的IC50高300倍以上，对JAK1和TYK2家族抑制效果不强。TG101348抑制有JAK2V617F突变的人红细胞白血病细胞系，以及一种表达人JAK2V617F（的Ba/F3 JAK2V617F）鼠前B细胞系的增殖，IC50分别是305 nM 和270 nM。G-101348也抑制亲本Ba/F3细胞的增殖至一般水平，IC50约为420 nM。TG101348降低STAT5磷酸化的浓度和抑制细胞增殖所需的浓度一致。TG101348以剂量依赖的方式诱导HEL和JAK2V617F Ba/F3细胞的凋亡。TG101348在浓度高达10 μM时对正常人真皮成纤维细胞没有促凋亡活性。[1] TG101348降低GATA-1的表达，这和erythroid-skewing JAK2V617F+祖细胞分化有关，并且抑制STAT5和GATA S310的磷酸化。[2] TG101348抑制HMC-1.1（KITV560G）细胞的增殖，活性低于HMC-1.2 (KITD816V, KITV560G)细胞，IC50分别为740 nM和407 nM。[3] |
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|---|---|---|---|---|
| 激酶实验 | 无细胞激酶活性测定 | |||
| TG101348 的IC 50值使用Invitrogen公司的223激酶试剂盒测定，其中包括JAK2和JAK2V617F，或者Carna Biosciences的所有Janus激酶家族成员试剂盒，包括JAK1和TYK2。ATP浓度设定为激酶的Km值。 | ||||
| 细胞实验 | 细胞系 | EpoBa/F3 JAK2V617F, Ba/F3p210, HEL和K562细胞 | ||
| 浓度 | 溶解在DMSO中至终浓度约10 μM | |||
| 孵育时间 | 72小时 | |||
| 方法 | 约2×103细胞接种到微量滴定板的孔中，加入含指定浓度抑制剂的100μLRPMI-1640培养基。TG101348温育72小时，50 μL XTT染料加入到每个孔中并孵育4小时，在CO2培养箱中培养。有色甲臜产物用分光光度法在450nm处测定在650nm处校正。50％的抑制作用（IC50）的浓度用GraphPad Prism 4.0软件确定。所有的实验都重复3次，并且结果和未处理的细胞的生长做比较。EpoBa/F3 JAK2V617F，Ba/F3p210，HEL和K562细胞凋亡是用DMSO和TG101348浓度的增加诱导来确定。 |
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| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | p-JAK2 / p-STAT1 / p-STAT3 / p-STAT6 / p-STAT5 / JAK2 c-Myc / PIM1 |
|
24610827 | |
| Growth inhibition assay | Cell proliferation |
|
24610827 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | TG101348有治疗JAK2V617F相关的骨髓增生性疾病(MPD)的潜力。在TG101348处理的动物中血细胞比容和白细胞计数有统计学显著减少，以剂量依赖性减少/消除髓外造血，至少在某些情况下，表现为衰减性骨髓纤维化，具有替代终点，包括减少/消除的JAK2V617F疾病负担，抑制内源性红细胞集落的形成相关，在体内抑制JAK-STAT信号转导。有没有明显的毒性并对T细胞数量无影响。[1] TG101348（120 mg/kg）口服显著抑制体内光伏红系祖细胞分化。[2] |
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|---|---|---|
| 动物实验 | Animal Models | C57BL / 6小鼠静脉注射表达JAK2V617F的全骨髓 |
| Dosages | 约120 mg/kg | |
| Administration | 口服，每天两次 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT04955938 | Recruiting | IDH Mutation|IDH1 Mutation|IDH2 Gene Mutation|Blood Cancer|Myeloproliferative Neoplasm |
University of Chicago |
October 29 2021 | Phase 1 |
| NCT05051553 | Completed | Healthy Volunteers |
Bristol-Myers Squibb |
September 21 2021 | Phase 1 |
| NCT04702464 | Completed | Healthy Volunteers |
Celgene|Impact Biomedicines Inc. a wholly owned subsidiary of Celgene Corporation |
January 12 2021 | Phase 1 |
| NCT03983161 | Completed | Healthy Volunteers|Hepatic Impairment |
Celgene|Impact Biomedicines Inc. a wholly owned subsidiary of Celgene Corporation |
September 4 2019 | Phase 1 |
| NCT03983239 | Completed | Healthy Volunteers |
Celgene|Impact Biomedicines Inc. a wholly owned subsidiary of Celgene Corporation |
June 21 2019 | Phase 1 |
化学信息&溶解度
| 分子量 | 524.68 | 分子式 | C27H36N6O3S |
| CAS号 | 936091-26-8 | SDF | Download Fedratinib (TG101348) SDF |
| Smiles | CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4 | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 100 mg/mL ( (190.59 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 |
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体内溶解配方 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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