product name Fedratinib (SAR302503)
Description: Fedratinib, also known as SAR302503 or TG101348, is a potent and selective inhibitor of janus kinase 2 (JAK2), with the inhibition constant IC50 of 3 nM. 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.
References: Cancer Cell. 2008 Apr;13(4):311-20; Cancer Cell. 2008 Apr;13(4):321-30; Leukemia. 2010 Jul;24(7):1378-80.
524.68
Formula
C27H36N6O3S
CAS No.
936091-26-8
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
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: 30 mg/mL
Synonyms
SAR302503, TG101348
other peoduct :
| In Vitro |
In vitro activity: 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. 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. 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. Kinase Assay: 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: Approximately 2 × 103 cells (EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562) 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. |
|---|---|
| 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. Oral administration of TG101348 (120 mg/kg) significantly inhibits PV progenitor erythroid differentiation in vivo. |
| Animal model | C57Bl/6 mice; C57BL/6 mice intravenously injected with whole bone marrow expressing JAK2V617F. |
| Formulation & Dosage | Dissolved in DMSO, and diluted in saline; 30, 100, and 200 mg/kg; administrated orally. |
| References | Cancer Cell. 2008 Apr;13(4):311-20; Cancer Cell. 2008 Apr;13(4):321-30; Leukemia. 2010 Jul;24(7):1378-80. |
