AT7519

Catalog No.S1524

AT7519 Chemical Structure

Molecular Weight(MW): 382.24

AT7519 is a multi-CDK inhibitor for CDK1, 2, 4, 6 and 9 with IC50 of 10-210 nM. It is less potent to CDK3 and little active to CDK7. Phase 2.

Size Price Stock Quantity  
In DMSO USD 170 In stock
USD 110 In stock
USD 210 In stock
USD 370 In stock
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3 Customer Reviews

  • Lysates of MDM treated with five-fold dilutions of the indicated compounds (starting concentration: AT7519, 0.5 mmol/l, roscovitine 4 mmol/l) were subjected to SDS-PAGE, transferred, and immunoblotted with antiphopho-SAMHD1, anti-SAMHD1 and anti-Hsp90 antibodies. MDM, monocyte-derived macrophage; SAMHD1, sterile a motif and HD domain-containing protein-1; SD, standard deviation.

    AIDS 2014 28(15), 2213-22. AT7519 purchased from Selleck.

    AT7519 drives eosinophil apoptosis and subsequent clearance by macrophages as assessed by morphological analysis. Representative images from vehicle (E) and AT7519 treated (F) animals are shown (Magnification x400 (i) and x1000 (ii and iii)). In vehicle treated animals (E), black arrows indicate healthy, viable eosinophils while in AT7519-treated animals (F), black arrows indicate typically apoptotic eosinophils and white arrows apoptotic cells inside macrophages.

    PLoS One 2011 6(9), e25683. AT7519 purchased from Selleck.

  • U87MG astroglioma cells were loaded with CFSE (5 μM) and treated with 0-400 nM of AT7519. Data acquired on day 0 and day 3 on a FACS Caliber flow cytometer and analysed by FlowJo. Results indicated that AT7519 partially inhibited cell proliferation. Higher than 400 nM resulted in cell death.

    Dr. Srinivas Narasipura of Rush University Medical Center. AT7519 purchased from Selleck.

Purity & Quality Control

Choose Selective CDK Inhibitors

Biological Activity

Description AT7519 is a multi-CDK inhibitor for CDK1, 2, 4, 6 and 9 with IC50 of 10-210 nM. It is less potent to CDK3 and little active to CDK7. Phase 2.
Targets
CDK9/CyclinT [1] CDK5/p35 [1] CDK2/CyclinA [1] GSK-3β [1] CDK4/CyclinD1 [1]
<10 nM 13 nM 47 nM 89 nM 100 nM
In vitro

AT7519 is an ATP competitive CDK inhibitor with a Ki value of 38 nM for CDK1. AT7519 is inactive against all non-CDK kinases with the exception of GSK3β (IC50 = 89 nM). AT7519 shows potent antiproliferative activity in a variety of human tumor cell lines with IC50 values ranging from 40 nM for MCF-7 to 940 nM for SW620 consistent with the inhibition of CDK1 and CDK2. [1] AT7519 induces dose-dependent cytotoxicity in multiple myeloma (MM) cell lines with IC50 values ranging from 0.5 to 2 μM at 48 hours, with the most sensitive cell lines being MM.1S (0.5 μM) and U266 (0.5 μM) and the most resistant MM.1R (>2 μM). It does not induce cytotoxicity in peripheral blood mononuclear cells (PBMNC). AT7519 partially overcomes the proliferative advantage conferred by IL6 and IGF-1 as well as the protective effect of bone marrow stromal cells (BMSCs). AT7519 induces rapid dephosphorylation of RNA pol II CTD at serine 2 and serine 5 sites, and leads to the inhibition of transcription, partially contributing to AT7519 induced cytotoxicity of MM cells. AT7519 induces activation of GSK-3β by down-regulating GSK-3β phosphorylation, which also contributes to AT7519 induced apoptosis independent of the inhibition of transcription. [2]

In vivo A twice daily dosing of AT7519 (9.1 mg/kg) causes tumor regression of both early-stage and advanced-stage s.c. tumors in the HCT116 and HT29 colon cancer xenograft models. [1] AT7519 treatment (15 mg/kg) inhibits tumor growth and prolongs the median overall survival of mice in the human MM xenograft mouse model in association with increased caspase 3 activation. [2]

Protocol

Kinase Assay:[1]
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In vitro Kinase Assays:

Kinase assays for CDK1, CDK2 and GSK3-β are all carried out in a radiometric filter binding format. Assays for CDK5 are in DELFIA format and for CDKs 4 and 6 in ELISA format. For CDKs 1 and 2, the relevant CDK and 0.12 μg/mL Histone H1 are incubated in 20 mM MOPS, pH 7.2, 25 mM β-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM sodium orthovanadate, 1 mM DTT, 0.1 mg/mL BSA, 45 μM ATP (0.78 Ci/mmol) and different concentrations of AT7519 for 2 or 4 hours respectively. For GSK3-β, the relevant enzyme and 5 μM glycogen synthase peptide 2 along with 10 mM MOPS pH 7.0, 0.1 mg/mL BSA, 0.001% Brij-35, 0.5% glycerol, 0.2 mM EDTA, 10 mM MgCl2, 0.01% β-mercaptoethanol, 15 μM ATP (2.31 Ci/mmol) and different concentrations of AT7519 are incubated for 3 hours. Assay reactions are stopped by adding an excess of orthophosphoric acid and filtered using Millipore MAPH filter plates. The plates are then washed, scintillant added and radioactivity measured by scintillation counting on a Packard TopCount. For CDK5, CDK5/p35 and 1μM of a biotinylated Histone H1 peptide (Biotin-PKTPKKAKKL) are incubated in 25 mM Tris-HCl, pH 7.5, 2.5 mM MgCl2, 0.025% Brij-35, 0.1 mg/mL BSA, 1 mM DTT, 15 μM ATP and different concentrations of AT7519 for 30 minutes. Assay reactions are stopped using EDTA, transferred to Neutravidin-coated plates and phosphorylated peptide quantified by means of a rabbit phospho-cdk1 substrate polyclonal antibody and DELFIA europium-labelled anti-rabbit IgG secondary antibody using time-resolved fluorescence at λex=335nm, λem=620nm. For CDK 4 and 6 assays, plates are coated with GST- pRb769-921 and blocked with Superblock. CDK4 or 6 is incubated with 15 mM MgCl2, 50 mM HEPES, pH 7.4, 1 mM DTT, 1 mM EGTA, pH 8.0, 0.02% Triton X-100, 2.5% DMSO and different concentrations of AT7519; the reaction is initiated by addition of ATP. After 30 minutes, reactions are stopped by the addition of 0.5 M EDTA pH 8.0. Plates are then washed and incubated for one hour with the primary antibody (anti- p-Rb Serine 780) diluted in Superblock followed by secondary antibody (alkaline phosphatase linked anti-rabbit) for a further hour. Plates are developed using the Attophos system and fluorescence read on a Spectramax Gemini plate reader at excitation 450 nm and emission 580 nm. In all cases, IC50 values are calculated from replicate curves, using GraphPad Prism software.
Cell Research:[2]
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  • Cell lines: MM.1S, MM.1R, RPMI8226, U266, RPMI8266, RPMI-Dox40, OPM1 cells, primary MM cells and PBMNCs
  • Concentrations: Dissolved in DMSO at a concentration of 10 mM, final concentrations 0.25-4 μM
  • Incubation Time: 24 or 48 hours
  • Method: Cells are incubated with different concentrations of AT7519 for 24 or 48 hours at 37 °C. Cell viability is assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrasodium bromide (MTT) dye absorbance. DNA synthesis is measured by tritiated thymidine uptake (3H-TdR). Apoptosis is assessed by using Annexin V/PI staining. The percentage of cells undergoing apoptosis is defined as the sum of early apoptosis (Annexin V-positive cells) and late apoptosis (Annexin V-positive and PI-positive cells
    (Only for Reference)
Animal Research:[2]
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  • Animal Models: Male SCID mice inoculated subcutaneously with MM.1S cells
  • Formulation: Dissolved in 0.9% saline
  • Dosages: 15 mg/kg/day
  • Administration: Dosed i.p.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 10 mg/mL (26.16 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W 30 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 Information

Molecular Weight 382.24
Formula

C16H17Cl2N5O2

CAS No. 844442-38-2
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02503709 Recruiting Metastatic Solid Neoplasm|Unresectable Solid Neoplasm National Cancer Institute (NCI) April 2016 Phase 1
NCT01652144 Completed Mantle Cell Lymphoma NCIC Clinical Trials Group|Astex Pharmaceuticals|Canadian Cancer Trials Group August 2012 Phase 2
NCT01627054 Completed Chronic Lymphocytic Leukemia NCIC Clinical Trials Group|Astex Pharmaceuticals|Canadian Cancer Trials Group August 2012 Phase 2
NCT01183949 Completed Multiple Myeloma Astex Pharmaceuticals|Multiple Myeloma Research Consortium November 2010 Phase 1|Phase 2
NCT00390117 Completed Lymphoma|Unspecified Adult Solid Tumor, Protocol Specific NCIC Clinical Trials Group|Canadian Cancer Trials Group August 2006 Phase 1

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