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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 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.
Targets |
JAK2 (IC50=3 nM)
JAK2 (V617F) (IC50=3 nM) Flt3 (IC50=15 nM) Ret (IC50=48 nM) |
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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].
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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].
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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. |
Molecular Formula |
C27H36N6O3S
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Molecular Weight |
524.6781
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Exact Mass |
524.25696021
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Elemental Analysis |
C, 61.81; H, 6.92; N, 16.02; O, 9.15; S, 6.11
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CAS # |
936091-26-8
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Related CAS # |
Fedratinib hydrochloride hydrate;1374744-69-0
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Appearance |
White to light yellow solid
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LogP |
4.8
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tPSA |
117Ų
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SMILES |
O=S(C1=CC=CC(NC2=NC(NC3=CC=C(OCCN4CCCC4)C=C3)=NC=C2C)=C1)(NC(C)(C)C)=O
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InChi Key |
JOOXLOJCABQBSG-UHFFFAOYSA-N
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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)
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Chemical Name |
N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide
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Synonyms |
Brand name Inrebic; SAR302503, TG101348; TG101348; TG 101348; TG-101348; SAR302503; SAR-302503; SAR 302503
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HS Tariff Code |
2934.99.9001
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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)
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Solubility (In Vitro) |
DMSO: 100 mg/mL (190.56mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.87 mg/mL (5.47 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.87 mg/mL (5.47 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: ≥ 2.08 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 6: 1% DMSO+30% polyethylene glycol+1% Tween 80:30mg/mL |
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.
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.
(2) Be sure to add the solvent(s) in order.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT05177211 | Recruiting | Drug: Fedratinib Pill | Myeloproliferative Neoplasm Chronic Neutrophilic Leukemia |
H. Lee Moffitt Cancer Center and Research Institute |
March 1, 2022 | Phase 2 |
NCT05524857 | Recruiting | Drug: Fedratinib Oral Capsule 300 mg Drug: Decitabine 20 mg/m2 |
RMyeloproliferative Neoplasm | Joseph Jurcic | January 28, 2022 | Phase 1 |
NCT04446650 | Active, not recruiting | Drug: Fedratinib | Primary Myelofibrosis | Celgene | October 12, 2020 | Phase 1 Phase 2 |
NCT06073847 | Recruiting | Drug: Fedratinib | Primary Myelofibrosis Post-polycythemia Vera Myelofibrosis |
Bristol-Myers Squibb | July 13, 2023 |