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Fedratinib

Fedratinib

产品编号 T1995   CAS 936091-26-8
别名: TG-101348, SAR 302503

Fedratinib (TG-101348) 是选择性,ATP 竞争性和具有口服活性的 JAK2抑制剂,对于 JAK2和JAK2V617F 激酶的IC50均为 3 nM。它是对JAK2的选择性分别比 JAK1 和 JAK3 高 35 倍和 334 倍。它可诱导癌细胞凋亡,并可用于骨髓增生性疾病的研究。

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Fedratinib Chemical Structure
Fedratinib, CAS 936091-26-8
规格 价格/CNY 货期 数量
2 mg ¥ 265 现货
5 mg ¥ 379 现货
10 mg ¥ 543 现货
25 mg ¥ 773 现货
100 mg ¥ 1,198 现货
200 mg ¥ 1,995 现货
500 mg ¥ 4,280 现货
1 mL * 10 mM (in DMSO) ¥ 481 现货
其他形式的 Fedratinib:
千万补贴 助力科研
BCA蛋白浓度测定试剂盒限时半价
Venetoclax限时半价
产品目录号及名称: Fedratinib (T1995)
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选择批次  
纯度: 99.96%
纯度: 99.9%
纯度: 99.73%
纯度: 99.41%
纯度: 99%
纯度: 98.23%
更多批次查询请联系客服
生物活性
化学信息
存储 & 溶解度
参考文献
产品描述 Fedratinib (TG-101348) (TG101348) is an ATP-competitive inhibitor of JAK2 (IC50: 3 nM) with significantly less potent activity against JAK3.
靶点活性 JAK2:3 nM (cell free), FLT3:15 nM (cell free), JAK2 (V617F):3 nM (cell free), RET:48 nM (cell free)
体外活性 Fedratinib (TG101348) inhibited proliferation of a human erythroblast leukemia (HEL) cell line that harbors the JAK2V617F mutation, as well as a murine pro-B cell line expressing human JAK2V617F (Ba/F3 JAK2V617F), with an IC50 value of approximately 300 nM for either line. Exposure of these cells to TG101348 reduced STAT5 phosphorylation at concentrations that parallel the concentrations required to inhibit cell proliferation [1]. TG101348 inhibited the proliferation of HMC-1.1 (KITV560G) cells, with somewhat lower potency than HMC-1.2 (KITD816V, KITV560G) cells, with IC50's of 740 and 407 nM, respectively. TG101348 did not inhibit phosphorylation of KITV560G or KITD816V within the context of the two HMC-1 clones at concentrations up to 25 μM. TG101348 potently inhibited JAK-STAT signaling in HMC-1.2 cells, the IC50 for JAK2 phosphorylation was 150 and 600 nM; the IC50 for STAT-5 and STAT-3 phosphorylation was ~600 nM [2].
体内活性 During the time course of the study, six animals died in the placebo group, and one animal in the 60 mg/kg drug group at day 18, whereas all animals treated with 120 mg/kg of TG101348 were all alive at study endpoint. There was a 2-fold decrease in JAK2V617F-positive CD71-single-positive early erythroid precursors in the bone marrow of animals at the 120 mg/kg dose compared with vehicle [1]. The maximum tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days [3].
激酶实验 IC50 values for TG101348 are determined commercially using the InVitrogen kinase profiling service for a 223 kinase screen that included JAK2 and JAK2V617F or Carna Biosciences for the screen of all Janus kinase family members including JAK1 and Tyk2. ATP concentration is set to approximately the Km value for each kinase [1].
细胞实验 Cells were treated with DMSO and increasing concentrations of inhibitor for 4 hr in RPMI-1640 before collected in 13 Cell Lysis Buffer, containing 1 mM PMSF, and protease inhibitor cocktail tablets. Protein lysates were quantified with BCA assay. Similar protein amounts were mixed with Laemmli sample buffer plus b-mercaptoethanol, boiled for 5 min, and separated on a 4%–15% Tris-HCl gradient electrophoresis gel. Gels were blotted onto a 0.45 mm nitrocellulose membrane, which was blocked in 5% nonfat dry milk and incubated with primary antibodies in either blocking solution or 5% BSA. The membranes were subsequently incubated with a mixture of donkey anti-rabbit IgG conjugated with infrared fluorophore (700 nm emission) and goat anti-mouse IgG conjugated with infrared fluorophore (800 nm emission). Following washing with PBS, the membranes were scanned on an Odyssey scanner to detect total (red) and phospho-STAT5 (green) proteins [1].
动物实验 The murine BM transplant model was generated and analyzed exactly as previously described. Briefly, C57BL/6 mice were intravenously injected with 1×10^6 whole bone marrow expressing JAK2V617F. Full development of disease was assessed with differential peripheral blood counts at day 26 after bone marrow transplantation. TG101348 was administered by oral gavage twice daily (b.i.d.) at 60 mg/kg, 120 mg/kg, or placebo from day 28 on for 42 days. Differential blood counts were assessed by retro-orbital nonlethal eye bleeds using EDTA glass capillary tubes before study initiation, during the study, and at study endpoints. C57/Bl6 mice were sacrificed at study endpoint or at times indicated based on an IUCAC-approved protocol that includes assessment of morbidity by > 10% loss of weight, scruffy appearance, lethargy, and/or splenomegaly extending across the midline. For histopathology, tissues were fixed in 10% neutral buffered formalin, embedded in paraffin, and stained with hematoxylin and eosin or, to assess for fibrosis, stained with reticulin. Images of histological slides were obtained on a Nikon Eclipse E400 microscope equipped with a SPOT RT color digital camera model 2.1.1. Images were analyzed in Adobe Photoshop 6.0. For flow cytometry, cells were washed in PBS, washed in 2% fetal bovine serum, blocked with Fc-Block for 10 min on ice, and stained with monoclonal antibodies in PBS and 2% FCS for 30 min on ice. Antibodies used were allophycocyanin (APC)-conjugated ter119, Gr-1, CD4, and B220 and phycoerythrin (PE)-conjugated, Mac1, CD8 (all 1:200), and CD71(1:100) rat anti-mouse. After washing, cells were resuspended in PBS and 2% FCS containing 0.5 mg/ml 7-amino-actinomycin D (7-AAD) to allow discrimination of nonviable cells. Flow cytometry was performed on a FACS Calibur cytometer, at least 10,000 events were acquired, and data were analyzed using FloJo software.The results are presented as graphs and representative dot plots of viable cells selected on the basis of scatter and 7-AAD staining [1].
别名 TG-101348, SAR 302503
化合物与蛋白结合的复合物

T1995_1

JAK2 JH1 in complex with Fedratinib

分子量 524.68
分子式 C27H36N6O3S
CAS No. 936091-26-8

存储

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

溶解度

DMSO: 93 mg/mL (177.3 mM)

H2O: < 1 mg/mL (insoluble or slightly soluble)

Ethanol: < 1 mg/mL (insoluble or slightly soluble)

溶液配制表

可选溶剂 浓度 体积 质量 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.9059 mL 9.5296 mL 19.0592 mL 47.6481 mL
5 mM 0.3812 mL 1.9059 mL 3.8118 mL 9.5296 mL
10 mM 0.1906 mL 0.953 mL 1.9059 mL 4.7648 mL
20 mM 0.0953 mL 0.4765 mL 0.953 mL 2.3824 mL
50 mM 0.0381 mL 0.1906 mL 0.3812 mL 0.953 mL
100 mM 0.0191 mL 0.0953 mL 0.1906 mL 0.4765 mL

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TargetMol Library Books参考文献

1. Wernig G, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008 Apr;13(4):311-20. 2. Lasho T, et al. Inhibition of JAK-STAT signaling by TG101348: a novel mechanism for inhibition of KITD816V-dependent growth in mast cell leukemia cells. Leukemia. 2010 Jul;24(7):1378-80. 3. Pardanani A, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011 Mar 1;29(7):789-96. 4. Zeng F, Chen H, Chen L, et al. An Autocrine Circuit of IL-33 in Keratinocytes is Involved in the Progression of Psoriasis[J]. Journal of Investigative Dermatology. 2020

TargetMol Library Books文献引用

1. Qian Y, Arellano G, Ifergan I, et al. ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis. Cell Reports. 2021, 36(8): 109602. 2. Ge H, Wang C, Tian C, et al. Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms. Biomedicine & Pharmacotherapy. 2022, 156: 113884 3. Zeng F, Chen H, Chen L, et al An Autocrine Circuit of IL-33 in Keratinocytes is Involved in the Progression of Psoriasis. Journal of Investigative Dermatology. 2020 4. Si H, Wang J, He R, et al. Identification of U937JAK3-M511I Acute Myeloid Leukemia Cells as a Sensitive Model to JAK3 Inhibitor. Frontiers in oncology. 2021, 11: 807200-807200. 5. Qin R, Wang T, He W, et al.Jak2/STAT6/c-Myc pathway is vital to the pathogenicity of Philadelphia-positive acute lymphoblastic leukemia caused by P190BCR-ABL.Cell Communication and Signaling.2023, 21(1): 27.
Bisindolylmaleimide VIII acetate CPTH2 VR23 Linifanib Puerarin 6''-O-Xyloside SCFSkp2-IN-2 Niraparib tosylate PF-3758309 hydrochloride

相关化合物库

该产品包含在如下化合物库中:
抗癌药物库 抑制剂库 抗癌临床化合物库 激酶抑制剂库 EMA 上市药物库 药物功能重定位化合物库 酪氨酸激酶分子库 抗癌上市药物库 FDA 上市激酶抑制剂库 干细胞分化化合物库

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Keywords

Fedratinib 936091-26-8 Angiogenesis Apoptosis Chromatin/Epigenetic JAK/STAT signaling Stem Cells Tyrosine Kinase/Adaptors FLT c-RET JAK STAT5 Inhibitor Janus kinase phosphorylation FLT3 myeloproliferative SAR-302503 JAK2V617F orally inhibit SAR302503 anti-proliferation JAK2 TG 101348 TG-101348 TG101348 RET anti-cancer SAR 302503 inhibitor

 

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