TG101209

Catalog No.S2692

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 in cell-free assays, ~30-fold selective for JAK2 than JAK3, sensitive to JAK2V617F and MPLW515L/K mutations.

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TG101209 Chemical Structure

TG101209 Chemical Structure
Molecular Weight: 509.67

Validation & Quality Control

Customer Product Validation(3)

Quality Control & MSDS

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  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

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 in cell-free assays, ~30-fold selective for JAK2 than JAK3, sensitive to JAK2V617F and MPLW515L/K mutations.
Targets JAK2 [1]
(Cell-free assay)
RET [1]
(Cell-free assay)
FLT3 [1]
(Cell-free assay)
JAK3 [1]
(Cell-free assay)
IC50 6 nM 17 nM 25 nM 169 nM
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 B200 nM. In a human JAK2V617F-expressing acute myeloid leukemia cell line, TG101209 inducs 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 triggered apoptosis of transformed Ba/F3 cells. [4]
In vivo 100 mg/kg of TG101209 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]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Cell-free Kinase Activity Assays IC50 values for TG101209 are determined using a luminescence-based kinase assay with recombinant JAK2, VEGFR2/KDR, and JAK3 obtained from Upstate Cell Signaling Solutions. Kinase reactions are carried out in a buffer consisting of 40mM Tris buffer (pH 7.4), 50mM MgCl2, 800M EGTA, 350M Triton X-100, 2M -mercaptoethanol, 100M peptide substrate, and an appropriate amount of JAK2, VEGFR2/KDR or JAK3 such that the assay is linear over 60 minutes. The reaction is initiated by the addition of 10L of ATP to a final concentration of 3mM and terminated by the addition of Kinase-Glo reagent after 60 minutes. Luciferase activity is quantified using an Ultra 384 instrument set for luminosity measurements. IC50 values are derived from experimental data using the non-linear curve fitting capabilities of the GraphPad Prism 4.0 software. The single concentration inhibition data for a panel of 63 kinases is determined using the SelectScreen TM service.

Cell Assay: [1]

Cell lines Ba/F3 cells expressing JAK2V617F (Ba/F3-EpoR-V617F) and MPLW515L (Ba/F3-W515L) mutants.
Concentrations 4.6-38 400 nM
Incubation Time 28-30 hours
Method 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 inhibited proliferation by 50%. All experiments are done in triplicate and the results normalized to growth of untreated cells.

Animal Study: [1]

Animal Models Ba/F3-V617F-GFP cells are injected into immunodeficient SCID mice to induce a rapidly fatal, fully penetrant hematopoietic disease.
Formulation TG101209 is dissolved in DMSO.
Dosages 100 mg/kg
Administration TG101209 is administered via oral gavage at the indicated doses beginning day +3 after tumor cell infusion and ending on day +20.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Pardanani A, et al, Leukemia, 2007, 21(8), 1658-1668.

[2] Ma AC, et al, Exp Hematol, 2009, 37(12), 1379-1386.

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Chemical Information

Download TG101209 SDF
Molecular Weight (MW) 509.67
Formula

C26H35N7O2S

CAS No. 936091-14-4
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 102 mg/mL (200.12 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% DMSO+30% polyethylene glycol+1% Tween 80 12 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide

Customer Product Validation (3)


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Rating
Source Leukemia 2014 28(7), 1519-28. TG101209 purchased from Selleck
Method Western blot analysis
Cell Lines Primary plasma cells
Concentrations 2 uM
Incubation Time 24 h
Results LCL161/TG101209 combination resulted in marked downregulation of pStat3, cIAP1, cIAP2 and XIAP when used on patient 5.

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Rating
Source Clin Cancer Res 2014 20(13), 3496-506. TG101209 purchased from Selleck
Method MTT assay
Cell Lines QGP1 cells
Concentrations 125 nM
Incubation Time 1 h
Results There was an additional decrease in survival when NU7026 was added to ERCC1 knockdown and/or EGFR inhibition (by gefitinib or siRNA) in combination with IR treatment. Addition of gefitinib treatment to NU7026 in combination with IR showed no difference in survival with treatment of gefitinib as a single agent which was highly statistically significant when compared with IR treatment alone.

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Rating
Source Claude HAAN Université du Luxembour. TG101209 purchased from Selleck
Method Western blot
Cell Lines HEL cells
Concentrations 0.25-1 μM
Incubation Time 3 h
Results TG101209 treatment resulted in a reduction of STAT5 phosphorylation in a concentration-dependent manner.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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