936091-26-8
936091-26-8 structure
- Name: Fedratinib(SAR302503,TG101348)
- Chemical Name: N-tert-butyl-3-[[5-methyl-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]pyrimidin-4-yl]amino]benzenesulfonamide
- CAS Number: 936091-26-8
- Molecular Formula: C27H36N6O3S
- Molecular Weight: 524.678
- Catalog: Biochemical Inhibitor Tyrosine protein kinase/signal transducer and transcriptional activator inhibitor (JAK/STAT) JAK inhibitor
- Create Date: 2018-12-31 12:33:49
- Modify Date: 2024-01-02 12:59:33
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Fedratinib (TG-101348) is a selective inhibitor of JAK2 with an IC50 of 3 nM, showing 35- and 334-fold selectivity over JAK1 and JAK3, respectively.
| Name | N-tert-butyl-3-[[5-methyl-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]pyrimidin-4-yl]amino]benzenesulfonamide |
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| Synonyms |
Fedratinib
TG-101348 N-(1,1-Dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]benzenesulfonamide N-(2-Methyl-2-propanyl)-3-{[5-methyl-2-({4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4-pyrimidinyl]amino}benzenesulfonamide SAR302503 TG 101348 Benzenesulfonamide, N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]- TG101348 N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzenesulfonamide 2TA |
| Description | Fedratinib (TG-101348) is a selective inhibitor of JAK2 with an IC50 of 3 nM, showing 35- and 334-fold selectivity over JAK1 and JAK3, respectively. |
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| Related Catalog | |
| Target |
JAK2:3 nM (IC50) JAK2(V617F):3 nM (IC50) Flt3:15 nM (IC50) Ret:48 nM (IC50) |
| In Vitro | Fedratinib (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. Fedratinib (TG-101348) 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. Fedratinib (TG-101348) also inhibits proliferation of parental Ba/F3 cells to a comparable level, with IC50 of appr 420 nM. Fedratinib (TG-101348) treatment reduces STAT5 phosphorylation at concentrations that parallel the concentrations required to inhibit cell proliferation. Fedratinib (TG-101348) induces apoptosis in both HEL and Ba/F3 JAK2V617F cells in a dose-dependent manner. Fedratinib 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]. Fedratinib (TG-101348) 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]. Fedratinib (TG-101348) 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 | Fedratinib (TG-101348) 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 Fedratinib (TG-101348) (120 mg/kg) significantly inhibits PV progenitor erythroid differentiation in vivo[2]. |
| Cell Assay | 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 Fedratinib, 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 Fedratinib. |
| Animal Admin | 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. Fedratinib (TG-101348) 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. |
| References |
| Density | 1.2±0.1 g/cm3 |
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| Boiling Point | 713.7±70.0 °C at 760 mmHg |
| Molecular Formula | C27H36N6O3S |
| Molecular Weight | 524.678 |
| Flash Point | 385.5±35.7 °C |
| Exact Mass | 524.256958 |
| PSA | 120.09000 |
| LogP | 3.27 |
| Vapour Pressure | 0.0±2.3 mmHg at 25°C |
| Index of Refraction | 1.611 |
| Storage condition | -20°C |
| HS Code | 29350090 |
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