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JAK/STAT
JAK inhibitor
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FLT3 inhibitor
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c-RET inhibitor
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Apoptosis related activator
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FLT inhibitor
Fedratinib (TG101348)
僅限科研使用
Fedratinib (TG101348)
別名: SAR302503
Fedratinib (SAR302503, TG101348)是一種選擇性JAK2抑制劑，在無細(xì)胞試驗(yàn)中IC50為3 nM，作用于JAK2比作用于JAK1和JAK3選擇性高35和334倍。Fedratinib也可抑制 FMS-like tyrosine kinase 3 (FLT3) 和 Ret (c-RET)，對應(yīng)的IC50值分別為15 nM和48 nM。Fedratinib有潛在的抗腫瘤活性。Fedratinib可抑制細(xì)胞增殖并促進(jìn)凋亡。Phase 2。
Fedratinib (TG101348) Chemical Structure
CAS: 936091-26-8
產(chǎn)品質(zhì)控
批次：
純度：
99.99%
99.99
常與Fedratinib (TG101348)一起在實(shí)驗(yàn)中被使用的化合物
Fedratinib和Pacritinib是FDA批準(zhǔn)的JAK2抑制劑，用于hydroxyurea/ruxolitinib治療失敗/血小板計(jì)數(shù)<50×10(9)/L的患者。
Fedratinib (TG101348)相關(guān)產(chǎn)品
相關(guān)信號通路圖
細(xì)胞實(shí)驗(yàn)數(shù)據(jù)示例
| 細(xì)胞系 | 實(shí)驗(yàn)類型 | 給藥濃度 | 孵育時(shí)間 | 活性描述 | 文獻(xiàn)信息(PMID) |
|---|---|---|---|---|---|
| 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 | ||
| 點(diǎn)擊查看更多細(xì)胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | Fedratinib (SAR302503, TG101348)是一種選擇性JAK2抑制劑，在無細(xì)胞試驗(yàn)中IC50為3 nM，作用于JAK2比作用于JAK1和JAK3選擇性高35和334倍。Fedratinib也可抑制 FMS-like tyrosine kinase 3 (FLT3) 和 Ret (c-RET)，對應(yīng)的IC50值分別為15 nM和48 nM。Fedratinib有潛在的抗腫瘤活性。Fedratinib可抑制細(xì)胞增殖并促進(jìn)凋亡。Phase 2。 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 靶點(diǎn) |
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| 體外研究(In Vitro) | ||||
| 體外研究活性 | TG-101348也顯著抑制JAK2 V617F, Flt3和Ret，IC50分別為3 nM, 15 nM和48 nM。TG101348對密切相關(guān)的JAK3的IC50高300倍以上，對JAK1和TYK2家族抑制效果不強(qiáng)。TG101348抑制有JAK2V617F突變的人紅細(xì)胞白血病細(xì)胞系，以及一種表達(dá)人JAK2V617F（的Ba/F3 JAK2V617F）鼠前B細(xì)胞系的增殖，IC50分別是305 nM 和270 nM。G-101348也抑制親本Ba/F3細(xì)胞的增殖至一般水平，IC50約為420 nM。TG101348降低STAT5磷酸化的濃度和抑制細(xì)胞增殖所需的濃度一致。TG101348以劑量依賴的方式誘導(dǎo)HEL和JAK2V617F Ba/F3細(xì)胞的凋亡。TG101348在濃度高達(dá)10 μM時(shí)對正常人真皮成纖維細(xì)胞沒有促凋亡活性。[1] TG101348降低GATA-1的表達(dá)，這和erythroid-skewing JAK2V617F+祖細(xì)胞分化有關(guān)，并且抑制STAT5和GATA S310的磷酸化。[2] TG101348抑制HMC-1.1（KITV560G）細(xì)胞的增殖，活性低于HMC-1.2 (KITD816V, KITV560G)細(xì)胞，IC50分別為740 nM和407 nM。[3] |
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|---|---|---|---|---|
| 激酶實(shí)驗(yàn) | 無細(xì)胞激酶活性測定 | |||
| TG101348 的IC 50值使用Invitrogen公司的223激酶試劑盒測定，其中包括JAK2和JAK2V617F，或者Carna Biosciences的所有Janus激酶家族成員試劑盒，包括JAK1和TYK2。ATP濃度設(shè)定為激酶的Km值。 | ||||
| 細(xì)胞實(shí)驗(yàn) | 細(xì)胞系 | EpoBa/F3 JAK2V617F, Ba/F3p210, HEL和K562細(xì)胞 | ||
| 濃度 | 溶解在DMSO中至終濃度約10 μM | |||
| 孵育時(shí)間 | 72小時(shí) | |||
| 方法 | 約2×103細(xì)胞接種到微量滴定板的孔中，加入含指定濃度抑制劑的100μLRPMI-1640培養(yǎng)基。TG101348溫育72小時(shí)，50 μL XTT染料加入到每個(gè)孔中并孵育4小時(shí)，在CO2培養(yǎng)箱中培養(yǎng)。有色甲臜產(chǎn)物用分光光度法在450nm處測定在650nm處校正。50％的抑制作用（IC50）的濃度用GraphPad Prism 4.0軟件確定。所有的實(shí)驗(yàn)都重復(fù)3次，并且結(jié)果和未處理的細(xì)胞的生長做比較。EpoBa/F3 JAK2V617F，Ba/F3p210，HEL和K562細(xì)胞凋亡是用DMSO和TG101348濃度的增加誘導(dǎo)來確定。 |
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| 實(shí)驗(yàn)圖片 | 檢測方法 | 檢測指標(biāo) | 實(shí)驗(yàn)圖片 | PMID |
| Western blot | p-JAK2 / p-STAT1 / p-STAT3 / p-STAT6 / p-STAT5 / JAK2 c-Myc / PIM1 |
|
24610827 | |
| Growth inhibition assay | Cell proliferation |
|
24610827 | |
| 體內(nèi)研究(In Vivo) | ||
| 體內(nèi)研究活性 | TG101348有治療JAK2V617F相關(guān)的骨髓增生性疾病(MPD)的潛力。在TG101348處理的動物中血細(xì)胞比容和白細(xì)胞計(jì)數(shù)有統(tǒng)計(jì)學(xué)顯著減少，以劑量依賴性減少/消除髓外造血，至少在某些情況下，表現(xiàn)為衰減性骨髓纖維化，具有替代終點(diǎn)，包括減少/消除的JAK2V617F疾病負(fù)擔(dān)，抑制內(nèi)源性紅細(xì)胞集落的形成相關(guān)，在體內(nèi)抑制JAK-STAT信號轉(zhuǎn)導(dǎo)。有沒有明顯的毒性并對T細(xì)胞數(shù)量無影響。[1] TG101348（120 mg/kg）口服顯著抑制體內(nèi)光伏紅系祖細(xì)胞分化。[2] |
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|---|---|---|
| 動物實(shí)驗(yàn) | Animal Models | C57BL / 6小鼠靜脈注射表達(dá)JAK2V617F的全骨髓 |
| Dosages | 約120 mg/kg | |
| Administration | 口服，每天兩次 | |
| 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 |
|
化學(xué)信息&溶解度
| 分子量 | 524.68 | 分子式 | C27H36N6O3S |
| CAS號 | 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 | ||
| 儲存條件(自收到貨起) | |||
|
體外溶解度 |
DMSO : 100 mg/mL ( (190.59 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(jì)算器 |
|
體內(nèi)溶解配方 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(jì)算器 | |||||
實(shí)驗(yàn)計(jì)算
摩爾濃度計(jì)算器
動物體內(nèi)配方計(jì)算器（澄清溶液）
第一步：請輸入基本實(shí)驗(yàn)信息（考慮到實(shí)驗(yàn)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(jì)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(jìn)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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