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TG101209

MCE China：TG101209

Brand：MedChemExpress (MCE)

Cat. No.HY-10410

CAS：936091-14-4

Purity：99.22%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：TG101209 is a selective JAK2 inhibitor with IC50 of 6 nM, less potent to Flt3 and RET with IC50 of 25 nM and 17 nM, appr 30-fold selective for JAK2 than JAK3, and sensitive to JAK2V617F and MPLW515L/K mutations.

In Vitro：TG101209 is an orally bioavailable, small molecule, ATP-competitive inhibitor towards several tyrosine kinases. TG101209 inhibits growth of Ba/F3 cells expressing JAK2V617F or MPLW515L mutations with an IC50 of 200 nM. In a human JAK2V617F-expressing acute myeloid leukemia cell line, TG101209 induces cell cycle arrest and apoptosis, and inhibits phosphorylation of JAK2V617F, STAT5 and STAT3. TG101209 suppresses growth of hematopoietic colonies from primary progenitor cells harboring JAK2V617F or MPL515 mutations[1]. TG101209 significantly reduces STAT5 phosphorylation without affecting the total amount of STAT5 protein[2]. TG101209 inhibits survivin and reduces phosphorylation of STAT3 in HCC2429 and H460 lung cancer cells. TG101209 results in radio sensitization of HCC2429 and H460 lung cancer cells in vitro[3]. A recent study indicates TG101209 abrogates BCR-JAK2 and STAT5 phosphorylation, decreases Bcl-xL expression and triggers apoptosis of transformed Ba/F3 cells[4].

In Vivo：TG101209 (100 mg/kg) effectively prolongs the survival in JAK2V617F-induced disease (10 days). Compared with placebo-treated animals, TG101209-treated animals exhibit statistically significant, dose-dependent reduction in the circulating tumor cell burden at day +11 to 20%[1].

Animal Administration：Severe combined immunodeficiency (SCID) mice are intravenously injected with 10 times 106 sorted GFP-positive BaF/3 cells expressing JAK2V617F (Ba/F3-V617F-GFP). TG101209 is administered by oral gavage at the indicated doses beginning day +3 after tumor cell infusion and ending on day +20. On day +11 following tumor cell injection, 1 mL blood is collected by terminal cardiac bleeding from the mouse that receives vehicle, and 0.1 mL of blood is collected by non-lethal retro-orbital collection from each of the three six-mouse groups dosed with 10, 30 or 100 mg/kg b.i.d. (twice daily) of TG101209, and samples pooled within the dose groups. Blood mononuclear cells are isolated by a Ficoll cushion centrifugation method (600 RCF and 30 min). The isolated cells are subjected to FACS analysis to determine the percentage of GFP-positive tumor cells (that is, Ba/F3-V617F-GFP cells).

Cell Assay：In brief, approximately 2×103 cells are plated into microtiterplate wells in 100 mL RPMI-1640 growth media with indicated concentrations of TG101209. The relative growth of cells is quantified at 24-hour intervals using Cell Proliferation Kit II (XTT) as per manufacturer's guidelines. After incubation, 20 mL of XTT is added to the wells and allowed to incubate for 4-6 hours. The colored formazan product is measured spectrophotometrically at 450 nm with correction at 650 nm, and IC50 values are determined using the GraphPad Prism 4.0 software. Data are subjected to a non-linear regression-fit analysis and IC50 values are determined as the concentration that inhibits proliferation by 50%. All experiments are done in triplicate and the results normalized to growth of untreated cells.

IC50 & Target：JAK2 6 nM (IC50) JAK3 169 nM (IC50) RET 17 nM (IC50) FLT3 25 nM (IC50)

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References：

[1]. Pardanani A, et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia. 2007 Aug;21(8):1658-68.  [Content Brief]

[2]. Ma AC, et al. A novel zebrafish jak2a(V581F) model shared features of human JAK2(V617F) polycythemia vera. Exp Hematol. 2009 Dec;37(12):1379-1386.e4.  [Content Brief]

[3]. Sun Y, et al. Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. J Thorac Oncol. 2011 Apr;6(4):699-706  [Content Brief]

[4]. Cuesta-Dominguez A, et al. Transforming and tumorigenic activity of JAK2 by fusion to BCR: molecular mechanisms of action of a novel BCR-JAK2 tyrosine-kinase. PLoS One. 2012;7(2):e3245  [Content Brief]