1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEFedratinibCat. No.: HY-10409CAS No.: 936091-26-8Synonyms: TG-101348; SAR 302503分式: CHNOS分量: 524.68作靶點: JAK作通路: Epigenetics; JAK/STAT Signaling; Stem Cell/Wnt儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶

2、解性數據體外實驗 DMSO : 42 mg/mL (80.05 mM)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (4.76 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.5 mg/mL (4.76 mM); Suspended solution; Need ultrasonic3. 請依序添加每種溶劑：

3、 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (4.76 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Fedratinib (TG-101348)JAK2 的選擇性抑制劑， IC50為3 nM，對JAK1和JAK3的選擇性35，334倍。IC50 & Target JAK2 JAK2(V617F) Flt3 Ret3 nM (IC50) 3 nM (IC50) 15 nM (IC50) 48 nM (IC50)體外研究 Fedratinib (TG-101348) significantly inhibits J

4、AK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48nM, respectively. TG101348 has an IC50 appr 300-fold higher for the closely related JAK3 and is a lesspotent inhibitor of the JAK1 and TYK2 family members. Fedratinib (TG-101348) inhibits proliferation of ahuman erythroblast leukemia (HEL) cel

5、l line that harbors the JAK2V617F mutation, as well as a murine pro-Bcell 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 ofappr 420 nM. Fedrati

6、nib (TG-101348) treatment reduces STAT5 phosphorylation at concentrations thatparallel the concentrations required to inhibit cell proliferation. Fedratinib (TG-101348) induces apoptosis inboth HEL and Ba/F3 JAK2V617F cells in a dose-dependent manner. Fedratinib does not show proapoptoticactivity in

7、 control normal human dermal fibroblasts at concentrations up to 10 M, and the antiproliferativeIC50 against fibroblasts is 5 M 1. Fedratinib (TG-101348) treatment decreases GATA-1 expression,which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibits STAT5 aswe

8、ll 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 of740 nM and 407 nM, respectively 3.體內研究 Fedratinib (TG-101348) has potential for efficacious treatment of J

9、AK2V617F-associated myeloproliferativediseases (MPD). In treated animals, there is a statistically significant reduction in hematocrit and leukocytecount, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in someinstances, evidence for attenuation of myelofibrosis

10、, correlated with surrogate endpoints, includingreduction/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 Tcell number 1. Oral administration of Fed

11、ratinib (TG-101348) (120 mg/kg) significantly inhibits PV progenitorerythroid differentiation in vivo 2.PROTOCOLCell Assay 1 Approximately 2103 cells are plated into microtiter-plate wells in 100 L RPMI-1640 growth media withindicated concentrations of inhibitor. Following 72 hours incubation with F

12、edratinib, 50 L of XTT dye areadded to each well and incubated for 4 hours in a CO2 incubator. The colored formazan product is measuredby spectrophotometry at 450 nm with correction at 650 nm. The concentration in which 50% of the effect (i.e.,2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEinhibit

13、ion of proliferation) is observed (IC50) is determined using the GraphPad Prism 4.0 software. Allexperiments are performed in triplicate, and the results are normalized to growth of untreated cells. Inductionof apoptosis of EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562 cells is determined by DNA frag

14、mentationwith DMSO and increasing concentrations of Fedratinib.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Briefly, C57BL/6 mice are intravenously injected with 1106 whole bone marrow expressing JAK2V617F. FullAdministration 1 development of

15、disease is assessed with differential peripheral blood counts at day 26 after bone marrowtransplantation. Fedratinib (TG-101348) is administered by oral gavage twice daily (b.i.d.) at 60 mg/kg, 120mg/kg, or placebo from day 28 on for 42 days. Differential blood counts are assessed by retro-orbitalno

16、nlethal eyebleeds using EDTA glass capillary tubes before study initiation, during the study, and at studyendpoints. C57/Bl6 mice are sacrificed at study endpoint or at times indicated based on an IUCAC-approvedprotocol that includes assessment of morbidity by 10% loss of weight, scruffy appearance,

17、 lethargy, and/orsplenomegaly extending across the midline. For histopathology, tissues are fixed in 10% neutral bufferedformalin, embedded in paraffin, and stained with hematoxylin and eosinor, to assess for fibrosis, stained withreticulin.MCE has not independently confirmed the accuracy of these m

18、ethods. They are for reference only.戶使本產品發表的科研獻 Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Cell Syst. 2018 Apr 25;6(4):424-443.e7. Mol Pharm. 2017 Jan 3;14(1):274-283. Molecules. 2018 Aug 18;23(8). pii: E2071. IUBMB Life. 2018 Jan;70(1):81-91.See more customer validations on HYPERLINK / www

19、.MedChemEREFERENCES1. Wernig G, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemiavera. Cancer Cell. 2008 Apr;13(4):311-20.2. Geron I, et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitor