1. Epigenetics
    Stem Cell/Wnt
    JAK/STAT Signaling
  2. JAK
    Epigenetic Reader Domain

TG-101348 (Synonyms: Fedratinib; SAR 302503)

Cat. No.: HY-10409 Purity: 98.28%
Data Sheet SDS Handling Instructions

TG-101348 is a selective inhibitor of JAK2 with IC50 of 3 nM, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3, and also inhibits BRD4 with IC50 of 340 nM.

For research use only. We do not sell to patients.
TG-101348 Chemical Structure

TG-101348 Chemical Structure

CAS No. : 936091-26-8

Size Price Stock Quantity
Free Sample (0.5-1 mg)   Apply now  
10 mM * 1 mL in DMSO $92 In-stock
5 mg $80 In-stock
10 mg $110 In-stock
50 mg $320 In-stock
100 mg $500 In-stock
200 mg   Get quote  
500 mg   Get quote  

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    TG-101348 purchased from MCE. Usage Cited in: Mol Pharm. 2017 Jan 3;14(1):274-283.

    Effects of Ponatinib and SAR302503 combination on BCR-ABL1 kinase and related proteins activity in the existence of IL-3. Western blot analysis on Ponatinib and SAR302503 treated BaF3/T315I cells for 2 h and stimulated with IL-3 stimulation (5 ng/mL) for 15 min. BCR-ABL1 phosphorylation is inhibited by Ponatinib while JAK2 and STAT5 are reactivated in the presence of IL-3. This reactivation is inhibited by low concentration of SAR302503. Ponatinib and SAR302503 combination deeply inhibits JAK2
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    TG-101348 is a selective inhibitor of JAK2 with IC50 of 3 nM, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3, and also inhibits BRD4 with IC50 of 340 nM.

    IC50 & Target

    IC50: 3 nM (JAK2), 340 nM (BRD4)

    In Vitro

    TG-101348 significantly inhibits JAK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48 nM, respectively. TG101348 has an IC50 appr 300-fold higher for the closely related JAK3 and is a less potent inhibitor of the JAK1 and TYK2 family members. TG101348 inhibits 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 IC50 of 305 nM and 270 nM, respectively. TG-101348 also inhibits proliferation of parental Ba/F3 cells to a comparable level, with IC50 of appr 420 nM. TG101348 treatment reduces STAT5 phosphorylation at concentrations that parallel the concentrations required to inhibit cell proliferation. TG101348 induces apoptosis in both HEL and Ba/F3 JAK2V617F cells in a dose-dependent manner. TG101348 does not show proapoptotic activity in control normal human dermal fibroblasts at concentrations up to 10 μM, and the antiproliferative IC50 against fibroblasts is >5 μM[1]. TG101348 treatment decreases GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibits STAT5 as well as GATA S310 phosphorylation[2]. TG101348 inhibits the proliferation of HMC-1.1 (KITV560G) cells, with somewhat lower potency than HMC-1.2 (KITD816V, KITV560G) cells, with IC50 of 740 nM and 407 nM, respectively[3].

    In Vivo

    TG101348 has potential for efficacious treatment of JAK2V617F-associated myeloproliferative diseases (MPD). In treated animals, there is a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis, correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction. There are no apparent toxicities and no effect on T cell number[1]. Oral administration of TG101348 (120 mg/kg) significantly inhibits PV progenitor erythroid differentiation in vivo[2].

    Clinical Trial
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    References
    Preparing Stock Solutions
    Concentration Volume Mass 1 mg 5 mg 10 mg
    1 mM 1.9059 mL 9.5296 mL 19.0592 mL
    5 mM 0.3812 mL 1.9059 mL 3.8118 mL
    10 mM 0.1906 mL 0.9530 mL 1.9059 mL
    Please refer to the solubility information to select the appropriate solvent.
    Kinase Assay
    [1]

    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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [1]

    TG-101348 is dissolved in DMSO.

    Approximately 2×103 cells are plated into microtiter-plate wells in 100 μL RPMI-1640 growth media with indicated concentrations of inhibitor. Following 72 hours incubation with TG101348, 50 μL of XTT dye are added to each well and incubated for 4 hours in a CO2 incubator. The colored formazan product is measured by spectrophotometry at 450 nm with correction at 650 nm. The concentration in which 50% of the effect (i.e., inhibition of proliferation) is observed (IC50) is determined using the GraphPad Prism 4.0 software. All experiments are performed in triplicate, and the results are normalized to growth of untreated cells. Induction of apoptosis of EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562 cells is determined by DNA fragmentation with DMSO and increasing concentrations of TG101348. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1]

    Briefly, C57BL/6 mice are intravenously injected with 1×106 whole bone marrow expressing JAK2V617F. Full development of disease is assessed with differential peripheral blood counts at day 26 after bone marrow transplantation. TG101348 is 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 are assessed by retro-orbital nonlethal eyebleeds using EDTA glass capillary tubes before study initiation, during the study, and at study endpoints. C57/Bl6 mice are 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 are fixed in 10% neutral buffered formalin, embedded in paraffin, and stained with hematoxylin and eosinor, to assess for fibrosis, stained with reticulin. Images of histological slides are obtained on a Nikon Eclipse E400 microscope equipped with a SPOT RT color digital camera model 2.1.1. Images are analyzed in Adobe Photoshop 6.0. For flow cytometry, cells are 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 are 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 are 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 is performed on a FACS Calibur cytometer, at least 10,000 events are acquired, and data are 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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    524.68

    Formula

    C₂₇H₃₆N₆O₃S

    CAS No.

    936091-26-8

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    DMSO: ≥ 42 mg/mL

    TG-101348 (SAR302503) is dissolved in aqueous solution containing 30% polyethylene glycol 200/2% Tween 80[4].

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    References

    Purity: 98.28%

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    Product Name:
    TG-101348
    Cat. No.:
    HY-10409
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