ArtNr |
S2736-5 |
Hersteller |
Selleckchem
|
CAS-Nr. |
936091-26-8 |
Menge |
5 mg |
Kategorie |
|
Typ |
Inhibitors |
Specific against |
other |
ECLASS 10.1 |
32160490 |
ECLASS 11.0 |
32160490 |
UNSPSC |
12000000 |
Alias |
SAR302503 |
Similar products |
TG101348 |
Lieferbar |
|
Administration |
Oral gavage twice daily (b.i.d.) |
Animal Models |
C57BL/6 mice injected intravenously with whole bone marrow expressing JAK2V617F |
Cell lines |
EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562 |
Chemical Name |
N-tert-butyl-3-(5-methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide |
Clinical Trials |
A Phase I/II study of TG-101348 in patients with primary or secondary myelofibrosis is ongoing. |
Concentrations |
Dissolved in DMSO, final concentrations ca.10 uM |
Description |
TG-101348 (SAR302503) is a selective inhibitor of JAK2 with IC50 of 3 nM. |
Dosages |
ca.120 mg/kg |
Formulation |
Dissolved in DMSO, and diluted in saline |
IC50 |
3 nM [1], 3 nM [1], 3 nM [1], 3 nM [1], 3 nM [1], 3 nM [1] |
In vitro |
TG-101348 also significantly inhibits JAK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48 nM, respectively. TG101348 has an IC50 ca.300-fold higher for the closely related JAK3 and is a less potent inhibitor of the JAK1 and TYK2 family members. TG101348 inhibits proliferation of a human erythroblast leukemia (HEL) cell line that harbors the JAK2V617F mutation, as well as a murine pro-B cell line expressing human JAK2V617F (Ba/F3 JAK2V617F), with IC50 of 305 nM and 270 nM, respectively. TG-101348 also inhibits proliferation of parental Ba/F3 cells to a comparable level, with IC50 of ca.420 nM. TG101348 treatment reduces STAT5 phosphorylation at concentrations that parallel the concentrations required to inhibit cell proliferation. TG101348 induces apoptosis in both HEL and Ba/F3 JAK2V617F cells in a dose-dependent manner. TG101348 does not show proapoptotic activity in control normal human dermal fibroblasts at concentrations up to 10 uM, and the antiproliferative IC50 against fibroblasts is >5 uM. [1] TG101348 treatment decreases GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibits STAT5 as well as GATA S310 phosphorylation. [2] TG101348 inhibits the proliferation of HMC-1.1 (KITV560G) cells, with somewhat lower potency than HMC-1.2 (KITD816V, KITV560G) cells, with IC50 of 740 nM and 407 nM, respectively. [3] |
In vivo |
TG101348 has potential for efficacious treatment of JAK2V617F-associated myeloproliferative diseases (MPD). In treated animals, there is a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis, correlated with surrogate endpoints, including reduction/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 T cell number. [1] Oral administration of TG101348 (120 mg/kg) significantly inhibits PV progenitor erythroid differentiation in vivo. [2] |
Incubation Time |
72 hours |
Kinase Assay |
Cell-free Kinase Activity Assays, IC50 values for TG101348 are determined commercially using the InVitrogen kinase profiling service for a 223 kinase screen that included JAK2 and JAK2V617F or Carna Biosciences for the screen of all Janus kinase family members including JAK1 and Tyk2. ATP concentration is set to approximately the Km value for each kinase. |
Method |
Approximately 2, 103 cells are plated into microtiter-plate wells in 100 uL RPMI-1640 growth media with indicated concentrations of inhibitor. Following 72 hours incubation with TG101348, 50 uL of XTT dye are added to each well and incubated for 4 hours in a CO2 incubator. The colored formazan product is 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) is determined using the GraphPad Prism 4.0 software. All experiments are performed in triplicate, and the results are normalized to growth of untreated cells. Induction of apoptosis of EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562 cells is determined by DNA fragmentation with DMSO and increasing concentrations of TG101348. |
Molecular Weight (MW) |
524, 68 |
Picture ChemicalStructure Description |
TG101348 (SAR302503) Chemical Structure |
Picture Description 1 |
, , Claude HAAN Universit du Luxembourg, TG101348 (SAR302503)purchased from Selleck |
Solubility (25C) |
DMSO 105 mg/mL, Water <1 mg/mL, Ethanol 21 mg/mL |
Storage |
2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO |
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