Fedratinib (SAR302503)

Alias: Brand name Inrebic; SAR302503, TG101348; TG101348; TG 101348; TG-101348; SAR302503; SAR-302503; SAR 302503
Cat No.:V0317 Purity: =100%
Fedratinib (formerly SAR302503 or TG101348; brand name Inrebic) is a novel, potent, selective, orally bioavailable, small-molecule and ATP-competitive inhibitor of janus kinase 2 (JAK2) with an IC50 of 3 nM.
Fedratinib (SAR302503) Chemical Structure CAS No.: 936091-26-8
Product category: JAK
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
5mg
25mg
100mg
250mg
500mg
1g
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Other Forms of Fedratinib (SAR302503):

  • Fedratinib (TG101348) dihydrochloride hydrate
Official Supplier of:
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Purity & Quality Control Documentation

Purity: =100%

Purity: ≥98%

Purity: ≥98%

Purity: ≥98%

Product Description

Fedratinib (formerly SAR302503 or TG101348; brand name Inrebic) is a novel, potent, selective, orally bioavailable, small-molecule and ATP-competitive inhibitor of janus kinase 2 (JAK2) with an IC50 of 3 nM. Fedratinib was approved by FDA in 2019 as an anticancer drug for the treatment of myeloproliferative diseases including myelofibrosis. The selectivity of TG101348 for JAK2 is 35- and 334-fold stronger than that for JAK3 and JAK1 respectively. TG10348 is capable of inducing apoptosis in HEL cells as well BaF/3 cells harboring JAK2V617 mutation and inhibiting hematopoietic progenitor colony formation and erythroid engraftment in samples from polycythemia vera (PV) patients.

Biological Activity I Assay Protocols (From Reference)
Targets
JAK2 (IC50=3 nM)
JAK2 (V617F) (IC50=3 nM)
Flt3 (IC50=15 nM)
Ret (IC50=48 nM)
ln Vitro
Fedratinib (TG101348) inhibits the proliferation of a human erythroblastic leukemia (HEL) cell line with the JAK2V617F mutation and a mouse pre-B cell line expressing human JAK2V617F (Ba/F3 JAK2V617F) with IC50 values of around 300 nM per line. Parental Ba/F3 cell growth was significantly reduced, with an IC50 value of around 420 nM [1]. Fedratinib (TG101348) at various dosages (0.1 μM, 0.3 μM, 1 μM, 3 μM, and 10 μM) lowered STAT5 phosphorylation to levels close to those needed to suppress cell proliferation [1]. Fedratinib (TG101348) (0.1 μM, 0.3 μM, 1 μM, 3 μM, and 10 μM) causes apoptosis in HEL and Ba/F3 JAK2V617F cells in a dose-dependent manner [1].
ln Vivo
In treated animals, fedratinib (TG101348; 60-120 mg/kg; oral gavage; twice daily; 42 days; C57Bl/6 mice) significantly reduced splenomegaly and reduced polycythemia in a dose-dependent manner [1].
Enzyme Assay
IC50 Determinations by Cell-free Kinase Activity Assays
IC50 values for TG101348 were determined commercially using the InVitrogen (Carlsbad, CA, USA) kinase profiling service for a 223 kinase screen that included JAK2 and JAK2V617F or Carna Biosciences (Kobe, Japan) for the screen of all Janus kinase family members including JAK1 and Tyk2. ATP concentration was set to approximately the Km value for each kinase.[1]
Cell Assay
XTT Assay for Cell Proliferation, Apoptosis, and DNA Laddering Assay
Approximately 2 × 103 cells were plated into microtiter-plate wells in 100 μl RPMI-1640 growth media with indicated concentrations of inhibitor. Following 72 hr incubation with TG101348, 50 μl of XTT dye were added to each well and incubated for 4 hr in a CO2 incubator. The colored formazan product was 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) was determined using the GraphPad Prism 4.0 software. All experiments were performed in triplicate, and the results were normalized to growth of untreated cells. Induction of apoptosis of EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562 cells was determined by DNA fragmentation with DMSO and increasing concentrations of inhibitor.
Western Blot Analysis
Cells were treated with DMSO and increasing concentrations of inhibitor for 4 hr in RPMI-1640 before collected in 1× Cell Lysis Buffer (Cell Signaling, Beverly, MA, USA), containing 1 mM PMSF, and protease inhibitor cocktail tablets (Roche). Protein lysates were quantified with Pierce Biotechnology BCA assay (Rockford, IL, USA). Similar protein amounts were mixed with Laemmli sample buffer (Bio-Rad Laboratories, Hercules, CA, USA) plus β-mercaptoethanol, boiled for 5 min, and separated on a 4%–15% Tris-HCL gradient electrophoresis gel (Bio-Rad Laboratories). Gels were blotted onto a 0.45 μm nitrocellulose membrane (Bio-Rad), 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 conjugate with infrared fluorophore (700 nm emission, LICOR) and goat anti-mouse IgG conjugated with infrared fluorophore (800 nm emission). Following washing with PBS, the membranes were scanned on a LICOR Odyssey scanner to detect total (red) and phospho-STAT5 (green) proteins.[2]
Animal Protocol
Animal/Disease Models: C57Bl/6 mice induced by the JAK2V617F mutation[1]
Doses: 60 mg/kg, 120 mg/kg
Route of Administration: po (oral gavage); twice (two times) daily; for 42 days
Experimental Results: demonstrated a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis.
References
[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]. Geron I, et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell. 2008 Apr;13(4):321-30.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C27H36N6O3S
Molecular Weight
524.6781
Exact Mass
524.25696021
Elemental Analysis
C, 61.81; H, 6.92; N, 16.02; O, 9.15; S, 6.11
CAS #
936091-26-8
Appearance
White to light yellow solid
LogP
4.8
tPSA
117Ų
SMILES
O=S(C1=CC=CC(NC2=NC(NC3=CC=C(OCCN4CCCC4)C=C3)=NC=C2C)=C1)(NC(C)(C)C)=O
InChi Key
JOOXLOJCABQBSG-UHFFFAOYSA-N
InChi Code
InChI=1S/C27H36N6O3S/c1-20-19-28-26(30-21-10-12-23(13-11-21)36-17-16-33-14-5-6-15-33)31-25(20)29-22-8-7-9-24(18-22)37(34,35)32-27(2,3)4/h7-13,18-19,32H,5-6,14-17H2,1-4H3,(H2,28,29,30,31)
Chemical Name
N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide
Synonyms
Brand name Inrebic; SAR302503, TG101348; TG101348; TG 101348; TG-101348; SAR302503; SAR-302503; SAR 302503
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 100 mg/mL (190.56mM) Water:<1 mg/mL Ethanol:<1 mg/mL
Solubility (In Vivo)
1% DMSO+30% polyethylene glycol+1% Tween 80:30mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 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

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Biological Data
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