Fedratinib，别名: SAR 302503, TG-

产品描述

Fedratinib (TG101348) is an ATP-competitive inhibitor of JAK2 (IC50: 3 nM) with significantly less potent activity against JAK3.

靶点活性

FLT3,15nM

JAK2,3nM

JAK2 (V617F),3nM

RET,48nM

实验溶液

1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL

体外活性

Fedratinib (TG101348) inhibited 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 an IC50 value of approximately 300 nM for either line. Exposure of these cells to TG101348 reduced STAT5 phosphorylation at concentrations that parallel the concentrations required to inhibit cell proliferation [1]. TG101348 inhibited the proliferation of HMC-1.1 (KITV560G) cells, with somewhat lower potency than HMC-1.2 (KITD816V, KITV560G) cells, with IC50’s of 740 and 407 nM, respectively. TG101348 did not inhibit phosphorylation of KITV560G or KITD816V within the context of the two HMC-1 clones at concentrations up to 25 μM. TG101348 potently inhibited JAK-STAT signaling in HMC-1.2 cells, the IC50 for JAK2 phosphorylation was 150 and 600 nM; the IC50 for STAT-5 and STAT-3 phosphorylation was ~600 nM [2].

体内活性

During the time course of the study, six animals died in the placebo group, and one animal in the 60 mg/kg drug group at day 18, whereas all animals treated with 120 mg/kg of TG101348 were all alive at study endpoint. There was a 2-fold decrease in JAK2V617F-positive CD71-single-positive early erythroid precursors in the bone marrow of animals at the 120 mg/kg dose compared with vehicle [1]. The maximum tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days [3].

激酶实验

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.

细胞实验

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.(Only for Reference)

细胞系： EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562

动物实验

动物模型：C57BL/6 mice injected intravenously with whole bone marrow expressing JAK2V617F

分子量

524.68

分子式

C27H36N6O3S

CAS

936091-26-8

溶解度

DMSO: 93 mg/mL (177.3 mM)

Ethanol: <1 mg/mL

Water: <1 mg/mL

（ < 1 mg/ml refers to the product slightly soluble or insoluble )

储存条件

store at -80°C

备注

For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.