Blood Cancer J. 2016 Oct 7;6(10):e481.
Expression of CALR mutants causes mpldependent thrombocytosis in zebrafish
TG101348 purchased from AbMole
|Source||Blood cancer journal (2016) . Figure 4. ruxolitinib (Abmole Bioscience, Houston, TX, USA) and fedratinib (Abmole Bioscience)|
|Cell Lines||Embroys of wild-type zebrafish|
|Concentrations||1 μM ~ 8 μM|
|Incubation Time||24 h|
|Results||The expression of CALRdel52 mRNA significantly increased stat5 phosphorylation (Figure 4a, lane 2). Furthermore, treatment with ruxolitinib and fedratinib significantly ameliorated the enhanced stat5 phosphorylation induced by CALR-del52 mRNA (Figure 4a, lane 3 and 4). In addition, treatment with ruxolitinib significantly decreased the numbers of CD41+ thrombocytes in uninjected control as well as CALR-del52-injected embryos in a dose-dependent manner (Figure 4b). Whereas treatment with fedratinib only had minimal inhibitory effect on the number of CD41+ thrombocytes in uninjected control embryos, and had a modest and significant dose-independent inhibitory effect on mutant CALR-induced thrombocytosis (Figure 4c). Our results demonstrated that mutant CALR-mediated pathogenic thrombopoiesis involves jak-stat activation that can be blocked by JAK inhibitors.|
|Cell lines||EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562 cells|
|Preparation method||XTT Assay for Cell Proliferation, Apoptosis, and DNA Laddering Assay Approximately 2 3 103 cells were plated into microtiter-plate wells in 100 ml RPMI-1640 growth media with indicated concentrations of inhibitor. Following 72 hr incubation with TG101348, 50 ml of XTT dye (Roche; Basel, Switzerland) 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.|
|Animal models||The murine BM transplant model with C57BL/6 mice|
|Dosages||twice daily (b.i.d.) at 60 mg/kg, 120 mg/kg from day 28 on for 42 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
JAK2 inhibitors and their impact in myeloproliferative neoplasms.
Geyer HL et al. Hematology. 2012 Apr;17 Suppl 1:S129-32. PMID: 22507800.
Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis.
Pardanani A et al. J Clin Oncol. 2011 Mar 1;29(7):789-96. PMID: 21220608.
Inhibition of JAK-STAT signaling by TG101348: a novel mechanism for inhibition of KITD816V-dependent growth in mast cell leukemia cells.
Lasho T et al. Leukemia. 2010 Jul;24(7):1378-80. PMID: 20485374.
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