ArtNr |
S1134-1000 |
Hersteller |
Selleckchem
|
CAS-Nr. |
896466-04-9 |
Menge |
1 g |
Kategorie |
|
Typ |
Inhibitors |
Specific against |
other |
ECLASS 10.1 |
32160490 |
ECLASS 11.0 |
32160490 |
UNSPSC |
12000000 |
Alias |
896466-04-9' |
Similar products |
AT9283 |
Lieferbar |
|
Administration |
Administered via i.p. |
Animal Models |
HCT116 cells are injected s.c. Into the hind flank of male BALB/c mice. |
Cell lines |
HCT 116 cells |
Chemical Name |
1-cyclopropyl-3-(3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)urea |
Clinical Trials |
AT9283 is currently in Phase I clinical trials in patients with Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma. |
Concentrations |
1 nM - 10 uM |
Description |
AT9283 is a potent pan-Aurora inhibitor for Aurora A, Aurora B, JAK3, JAK2 and Abl with IC50 of 3 nM, 3 nM, 1.1 nM, 1.2 nM and 4 nM, respectively. |
Dosages |
15 mg/kg and 20 mg/kg |
Formulation |
Belinostat is dissolved in 10% DMSO, 20% water, 70% hydroxypropyl- beta-cyclodextrin (25% w/v aq). |
IC50 |
3 nM, 3 nM, 3 nM, 3 nM, 3 nM, 3 nM |
In vitro |
AT9283 leads to a clear polyploid phenotype by inhibiting the activity of Aurora B kinase in HCT116 cells with IC50 of 30 nM. Furthermore, AT9283 also produces the potent inhibition on HCT116 colony formation. [1] |
In vivo |
In HCT116 human colon carcinoma xenograft bearing mice, AT9283 treatment (15 mg/kg and 20 mg/kg) for 16 days results in a significant tumor growth inhibition of 67% and 76%, respectively. In addition, AT9283 also exhibits a significantly longer half-life in tumors(2.5 hours) compared with plasma (0.5 hour) and modest oral bioavailability in mice (Fp.o. = 24%). [1] |
Incubation Time |
72 hours |
Kinase Assay |
Aurora A and Aurora B Kinase Assays, Assays for Aurora A and B are performed in a DELFIA format. Aurora A enzyme is incubated with AT9283 and 3 uM cross-tide substrate (biotin-CGPKGPGRRGRRRTSSFAEG) in 10 mM MOPS, pH 7, 0.1 mg/mL BSA, 0.001% Brij-35, 0.5% glycerol, 0.2 mM EDTA, 10 mM MgCl2, 0.01% beta-mercaptoethanol, 15 uM ATP, and 2.5% DMSO. Aurora B enzyme is incubated with AT9283, 3 uM of the above substrate in 25 mM Tris, pH 8.5, 5 mM MgCl2, 0.1 mg/mL BSA, 0.025% Tween-20, 1 mM DTT, 15 uM ATP, and 2.5% DMSO. Reactions are allowed to proceed for 60 minutes and 45-90 minutes for Aurora A and Aurora B, respectively, before quenching with EDTA. The reaction mixtures are then transferred to a neutravidin-coated plate, and phosphorylated peptide is quantified by means of a phospho-specific antibody and a europium labeled secondary antibody using time-resolved fluorescence (excitation, 337 nm, emission, 620 nm). IC50 values for the control compounds are 92 nM (Aurora A assay) and 17 nM (Aurora B). |
Method |
HCT 116 cells are cultured in DMEM + 10% FBS + GLUTAMAX I. Black 96-well flat-bottomed (clear) tissue culture treated plates are seeded in 200 L of medium and incubated for approximately 16 hours at 37C in a humidified atmosphere of 5% CO2 in air. Cells are treated with test compound at nine different concentrations (spanning 1 nM to 10 M, plus DMSO vehicle control) and then incubated for 72 hours. Polyploidy morphological observations of the cells are then noted. The concentration of AT9283 required to produce a distinct polyploid phenotype is reported. Cells are seeded at a concentration of 75100 cells/mL relevant culture media onto 6- or 24-well tissue culture plates and allowed to recover for 16 hours. Test compound (11 concentrations spanning 0.1 nM to 10 M) or vehicle control (DMSO) is added to duplicate wells to give a final DMSO concentration of 0.1%. Following compound addition, colonies are allowed to grow between 10 and 14 days for optimum discrete colony counting. Colonies are fixed in 2 mL of Carnoys fixative (25% acetic acid, 75% MeOH) and stained in 2 mL of 0.4% w/v crystal violet. The numbers of colonies in each well is counted. IC50 values are calculated by sigmoidal dose-response (variable slope) IC50 curves using Prism Graphpad software. |
Molecular Weight (MW) |
381, 43 |
Picture ChemicalStructure Description |
AT9283 Chemical Structure |
Picture Description 1 |
, , Dr. Claude Haan and Catherine Rolvering of Universite du Luxembourg, AT9283purchased from Selleck, HEL cells were treated for 3 hours with the indicated concerntrations of AT9283. AT9283 inhibitors Jak2-V617F mediated signal transduction at submicromolar concentrations in intact cells . At concentrations of 490 nm the Jak2-V617F inhibition is almost complete and has reached almost background levels (for background STAT5 phosphorylation see 4400nm) |
Solubility (25C) |
DMSO 76 mg/mL, Water <1 mg/mL, Ethanol 38 mg/mL |
Storage |
2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO |
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