TG101209, an orally bioavailable JAK2 inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. TG101209 potently inhibits JAK2 (IC(50)=6 nM), FLT3 (IC(50)=25 nM) and RET (IC(50)=17 nM) kinases, with significantly less activity against other tyrosine kinases including JAK3 (IC(50)=169 nM). TG101209 also inhibited STAT3 activation and survivin expression, and sensitized HCC2429 (DER=1.34, p=0.002) and H460 (DER=1.09, p=0.006) cells to radiation in clonogenic assays. In vivo, addition of TG101209 to radiation in lung xenografts produced a significant tumor growth delay (>10 days). TG101209 has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells.
|Cell lines||Ba/F3 cells, MPLW515L, CTLL-2 cells and HEL and K562 cells|
|Preparation method||XTT assay for cell proliferation.
In brief, approximately 2*103 cells were plated into microtiterplate wells in 100 ml RPMI-1640 growth media with indicated concentrations of inhibitor. The relative growth of cells was quantified at 24-h intervals using Cell Proliferation Kit II (XTT) as per manufacturer’s guidelines (Roche, Indianapolis, IN, USA). After incubation, 20 ml of XTT was added to the wells and allowed to incubate for 4–6 h. The colored formazan product was measured spectrophotometrically at 450 nm with correction at 650 nm, and IC50 values were determined using the GraphPad Prism 4.0 software. Data were subjected to a non-linear regression-fit analysis and IC50 values were determined as the concentration, that inhibited proliferation by 50%. All experiments were done in triplicate and the results normalized to growth of untreated cells.
|Concentrations||0~100 μ M|
|Incubation time||24 h|
|Animal models||JAK2V617F-induced hematopoietic disease in a nude mouse model|
|Dosages||10, 30 and 100mg/kg bid|
|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.
|Solubility||DMSO 100 mg/mL|
TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells.
Ramakrishnan V, et al. Am J Hematol. 2010 Sep;85(9):675-86. PMID: 20652971.
TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations.
Pardanani A, et al. Leukemia. 2007 Aug;21(8):1658-68. PMID: 17541402.
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Oclacitinib is a novel inhibitor of JAK family members with IC50 ranging from 10 to 99 nM and JAK1-dependent cytokines with IC50 ranging from 36 to 249 nM, which did not inhibit a panel of 38 non-JAK kinases.
Baricitinib phosphate(INCB 028050; LY 3009104) is a selective JAK1 and JAK2 inhibitor with IC50 of 5.9 nM and 5.7 nM, ~70 and ~10-fold selective versus JAK3 and Tyk2, no inhibition to c-Met and Chk2.
Janex-1 is a cell-permeable, reversible, potent, ATP-competitive, and specific inhibitor of JAK3 (IC50 = 78 μM); has no effect on JAK1, JAK2, or Zap/Syk or SRC tyrosine kinases.
Decernotinib is a potent and selective Janus kinase 3 (JAK3) inhibitor with Ki of 2.5 nM; IC50 is 50-170 nM in cellular assays.
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