Fedratinib (TG101348)

Catalog No.S2736 Batch:S273603

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Technical Data

Formula

C27H36N6O3S

Molecular Weight 524.68 CAS No. 936091-26-8
Solubility (25°C)* In vitro DMSO 100 mg/mL (190.59 mM)
Ethanol 10 mg/mL (19.05 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description Fedratinib (SAR302503, TG101348) is a selective inhibitor of JAK2 with IC50 of 3 nM in cell-free assays, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3. Fedratinib also inhibits FMS-like tyrosine kinase 3 (FLT3) and RET (c-RET) with IC50 of 15 nM and 48 nM, respectively. Fedratinib has potential antineoplastic activity. Fedratinib inhibits proliferation and induces apoptosis. Phase 2.
Targets
JAK2 [1]
(Cell-free assay)
JAK2 (V617F) [1]
(Cell-free assay)
FLT3 [1]
(Cell-free assay)
RET [1]
(Cell-free assay)
3 nM 3 nM 15 nM 48 nM
In vitro

TG-101348 also significantly inhibits JAK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48 nM, respectively. TG101348 has an IC50 ~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 ~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]

Protocol (from reference)

Kinase Assay:

[1]

  • Cell-free Kinase Activity Assays

    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.

Cell Assay:

[1]

  • Cell lines

    EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562

  • Concentrations

    Dissolved in DMSO, final concentrations ~10 μM

  • Incubation Time

    72 hours

  • Method

    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.

Animal Study:

[1]

  • Animal Models

    C57BL/6 mice injected intravenously with whole bone marrow expressing JAK2V617F

  • Dosages

    ~120 mg/kg

  • Administration

    Oral gavage twice daily (b.i.d.)

Customer Product Validation

Data from [Data independently produced by Blood, 2014, 123(20), 3175-84]

Data from [Cancer Gene Ther, 2013, 20, 582-9]

, , Claude HAAN Université du Luxembour

Data from [Data independently produced by , , J Thorac Oncol, 2016, 11(1):62-71]

Selleck's Fedratinib (TG101348) has been cited by 87 publications

Extracellular-vesicle-packaged S100A11 from osteosarcoma cells mediates lung premetastatic niche formation by recruiting gMDSCs [ Cell Rep, 2024, 43(2):113751] PubMed: 38341855
Integrated drug response prediction models pinpoint repurposed drugs with effectiveness against rhabdomyosarcoma [ PLoS One, 2024, 19(1):e0295629] PubMed: 38277404
FGF19-Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer [ Adv Sci (Weinh), 2023, 10(24):e2302613] PubMed: 37345586
JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States [ Cancer Res, 2023, 83(2):264-284] PubMed: 36409824
CRISPR/Cas9-engineering of HMC-1.2 cells renders a human mast cell line with a single D816V-KIT mutation: An improved preclinical model for research on mastocytosis [ Front Immunol, 2023, 14:1078958] PubMed: 37025992
A newly identified 45-kDa JAK2 variant with an altered kinase domain structure represents a novel mode of JAK2 kinase inhibitor resistance [ Mol Oncol, 2023, 18(2):415-430.] PubMed: 38104968
Genome-wide open reading frame profiling identifies fibroblast growth factor signaling as a driver of PD-L1 expression in head and neck squamous cell carcinoma [ Oral Oncol, 2023, 146:106562] PubMed: 37666053
Interleukin-29 Accelerates Vascular Calcification via JAK2/STAT3/BMP2 Signaling [ J Am Heart Assoc, 2023, 12(1):e027222] PubMed: 36537334
Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice [ Drug Metab Dispos, 2023, 10.1124/dmd.123.001360] PubMed: 37562957
Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice [ Drug Metab Dispos, 2023, 51(11):1483-1489] PubMed: 37562957

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SHIPPING AND STORAGE
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