KU-55933 Chemical Properties

Boiling point:

628.0±55.0 °C(Predicted)

Density 

1.419±0.06 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (up to 40 mg/ml) or in Ethanol (up to 20 mg/ml)

form 

powder

pka

0.33±0.20(Predicted)

color 

white to beige

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 1 month.

InChI

InChI=1S/C21H17NO3S2/c23-14-12-16(25-20(13-14)22-8-10-24-11-9-22)15-4-3-7-19-21(15)27-18-6-2-1-5-17(18)26-19/h1-7,12-13H,8-11H2

InChIKey

XRKYMMUGXMWDAO-UHFFFAOYSA-N

SMILES

C1(N2CCOCC2)OC(C2=C3C(SC4=C(S3)C=CC=C4)=CC=C2)=CC(=O)C=1

Safety Information

WGK Germany 

3

KU-55933 Usage And Synthesis

Description

Potent and selective ATM kinase inhibitor IC50s= 13, 2500, 9300, 16600, >100000 and >100000 nM for ATM, DNA-PK, mTOR, PI 3-kinase, PI 4-K and ATR respectively.1Decreases viability of MCF-7, A549 and HCT116 cells and decreases p21CIP1?levels?in vitro.2?Disruption of ATM signaling in primary A-T fibroblasts leads to dysregulation of ribonucleotide reductase and increase resistance to inhibitors of mitochondrial respiration and translation.3?Sensitizes radio-resistant cancer cells.4Provides neuroprotection against H2O2-induced cell damage.5

Uses

A potent and specific ATM kinase inhibitor with an IC50 and a Ki of 13 nM and 2.2 nM, respectively.

Uses

KU-55933 has been used as an ataxia-telangiectasia mutated (Atm) inhibitor.

Definition

ChEBI: 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone is a thianthrene.

Biological Activity

Potent, selective and competitive ATM kinase inhibitor (K i = 2.2 nM, IC 50 values are 13, 2500, 9300, 16600, > 100000 and > 100000 nM at ATM, DNA-PK, mTOR, PI 3-kinase, PI 4-K and ATR respectively). Decreases viability of MCF-7, A549 and HCT116 cells and decreases p21 CIP1 levels in vitro . Acts as a radio- and chemosensitizer for the treatment of cancer.

Biochem/physiol Actions

KU-55933 is a very potent, specific inhibitor of Ataxia telangiectasia (A-T) mutated (ATM) kinase (IC50 = 13 nM). KU-22933 treatment sensitizes cancer cells to ionizing radiation and cytotoxic drugs. The compound KU-22933 blocks ATM-mediated phosphorylyation of p53, gH2AX, NBS1, and SMC1.

Synthesis

Example 1 Synthesis of 2-morpholin-4-yl-6-thianthren-1-ylpyran-4-one (4): 2-chloro-6-morpholin-4-ylpyran-4-one (3) (863 mg, 4 mmol), thiophene-1-boronic acid (1.145 g, 4.4 mmol), and milled potassium carbonate (1.105 g, 8 mmol) were suspended in dioxane (10 mL) and degassed (sonicated for 5 min and subsequently saturated with N2). Tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) was then added and the reaction mixture was stirred vigorously at 90 °C for 24 h under N2 protection. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was suspended in water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (silica gel; eluent: ethyl acetate/ethanol = 9:1) to afford 2-morpholin-4-yl-6-thianthren-1-ylpyran-4-one as a white solid (70 mg, 4% yield).1H NMR (300 MHz, DMSO-d6) δ: 3.44 (4H, t, J=5 Hz), 3.76 (4H, t , J=5 Hz), 5.57 (1H, d, J=2 Hz), 6.30 (1H, d, J=2 Hz), 7.43 (2H, m), 7.53 (1H, t, J=8 Hz), 7.66 (3H, m), 8.49 (1H, dd, J=1, 8 Hz). Mass spectrum (LC-MS, ESI): m/z 396 [M+H]+.

storage

Desiccate at -20°C

References

[1] IAN HICKSON. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM.[J]. Cancer research, 2004, 64 24: 9152-9159. DOI:10.1158/0008-5472.can-04-2727
[2] ELVIRA CRESCENZI. Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy.[J]. Clinical Cancer Research, 2008, 14 6: 1877-1887. DOI:10.1158/1078-0432.ccr-07-4298
[3] JANA S EATON. Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis.[J]. Journal of Clinical Investigation, 2007, 117 9: 2723-2734. DOI:10.1172/jci31604
[4] TINGTING ZHANG. The ATM inhibitor KU55933 sensitizes radioresistant bladder cancer cells with DAB2IP gene defect.[J]. International Journal of Radiation Biology, 2015, 91 4: 368-378. DOI:10.3109/09553002.2015.1001531
[5] JAKUB CHWASTEK  Władysław L  Danuta Jantas. The ATM kinase inhibitor KU-55933 provides neuroprotection against hydrogen peroxide-induced cell damage via a γH2AX/p-p53/caspase-3-independent mechanism: Inhibition of calpain and cathepsin D[J]. International Journal of Biochemistry & Cell Biology, 2017, 87: Pages 38-53. DOI:10.1016/j.biocel.2017.03.015

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