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KU-55933

KU-55933 is a potent and specific ATM inhibitor with IC50 and Ki of 13 nM and 2.2 nM, respectively.

Catalog No.S1092
5 5 3 Reviews 11 Product Citations
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KU-55933 Chemical Structure
Molecular Weight: 395.49

Validation & Quality Control

Customer Reviews(3)

Quality Control & MSDS

Related Compound Libraries

KU-55933 is available in the following compound libraries:

Cambridge Cancer Compound Library(96-well) Chemical Library (96-well) Inhibitor Library (96-well) Kinase Inhibitor Library (96-well)

Product Information

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Product Description

Biological Activity Protocol Chemical Information Customer Reviews Product Citations Tech Support & FAQs

Biological Activity

Description KU-55933 is a potent and specific ATM inhibitor with IC50 and Ki of 13 nM and 2.2 nM, respectively.
Targets ATM ATM
IC50 13 nM 2.2 nM (Ki) [1]
In vitro KU-55933 inhibits DNA-PK and PI3K with IC50 of 2.5 μM and 16.6 μM, respectively. Besides, KU-55933 also prevents the activity of mTOR with IC50 of 9.3 μM. KU-55933 is active at the cellular level in ablating a well-characterized ATM-dependent phosphorylation event. KU-55933 has a dose-dependent effect in inhibiting this ATM-dependent phosphorylation event with IC50 of 300 nM. KU-58050 does not prevent the ATM-dependent phosphorylation of p53 serine 15 until a dose of 30 μM. Addition of KU-55933 has no appreciable effects on UV-induced phosphorylation of H2AX on serine 139, NBS1 on serine 343, CHK1 on serine 345, and SMC1 on serine 966. In stark contrast to the UV responses, KU-55933 ablates the ionizing radiation-induced phosphorylation of these ATM substrates. KU-55933 sensitizes HeLa cells to a range of ionizing radiation doses. [1] KU-55933 inhibits the phosphorylation of Akt induced by growth factors in cancer cells. KU-55933 suppresses the proliferation of cancer cells. Furthermore, suppression of ATM by KU-55933 improves survival, probably via prevention of downstream activation of TAp63α. [2]
In vivo Suppression of ATM-dependent STAT3 activation by KU-55933 enhances TRAIL-mediated apoptosis through up-regulation of surface DR5 expression, whereas suppression of both STAT3 and NF-κB appeares to be involved in down-regulation of cFLIP accompanied by an additional increase in apoptotic levels. The ATM inhibitor KU-55933 affectes TRAIL-mediated apoptosis more strongly than the JAK2 inhibitor, AG490, or overexpression of STAT3β. [3]
Clinical Trials
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Purified enzyme assays ATM for use in the in vitro assay is obtained from HeLa nuclear extract by immunoprecipitation with rabbit polyclonal antiserum raised to the COOH-terminal 400 amino acids of ATM in buffer containing 25 mM HEPES (pH 7.4), 2 mM MgCl2, 250 mM KCl, 500 μM EDTA, 100 μM Na3VO4, 10% v/v glycerol, and 0.1% v/v Igepal. ATM-antibody complexes are isolated from nuclear extract by incubating with protein A-Sepharose beads for 1 hour and then through centrifugation to recover the beads. In the well of a 96-well plate, ATM-containing Sepharose beads are incubated with 1 μg of substrate glutathione S-transferase–p53N66 (NH2-terminal 66 amino acids of p53 fused to glutathione S-transferase) in ATM assay buffer [25 mM HEPES (pH 7.4), 75 mM NaCl, 3 mM MgCl2, 2 mM MnCl2, 50 μM Na3VO4, 500 μM DTT, and 5% v/v glycerol] at 37 °C in the presence or absence of inhibitor. After 10 minutes with gentle shaking, ATP is added to a final concentration of 50 μM and the reaction continued at 37 °C for an additional 1 hour. The plate is centrifuged at 250 × g for 10 minutes (4 °C) to remove the ATM-containing beads, and the supernatant is removed and transferred to a white opaque 96-well plate and incubated at room temperature for 1.5 hours to allow glutathione S-transferase-p53N66 binding. This plate is then washed with PBS, blotted dry, and analyzed by a standard ELISA technique with a phospho-serine 15 p53 antibody. The detection of phosphorylated glutathione S-transferase-p53N66 substrate is performed in combination with a goat antimouse horseradish peroxidase-conjugated secondary antibody. Enhanced chemiluminescence solution is used to produce a signal and chemiluminescent detection is carried out.

Cell Assay: [1]

Cell lines U2OS cells
Concentrations 10 μM
Incubation Time 2 hours
Method U2OS cells are exposed to ionizing radiation (3, 5, or 15 Gy) or UV (5 or 50 J/m2) and the ATM response determined by Western blot analysis of p53 serine 15 phosphorylation and stabilization of wild-type p53. Whole cell extracts are obtained from each time point, proteins separated by SDS-PAGE, and the ATM-specific increase in phosphorylated serine 15 measured with a p53 phospho-serine 15 specific antibody. Overall p53 stabilization with time is also observed with a p53-specific antibody (DO-1). Similarly, for studying ATM-dependent phosphorylations on H2AX, CHK1, NBS1, and SMC1, the following antibodies are used: CHK1 phospho-serine 345 and NBS1 phospho-serine 343 antibodies. Histone H2A (H-124) and CHK1 antibodies are also used, as well as SMC1 and SMC1 phospho-serine 966 antibodies. For determination of a cellular IC50 for KU-55933, the peak response time for p53 serine 15 phosphorylation of 2 hours is used to monitor inhibition of ATM. KU-55933 is titrated onto cells and preincubated for 1 hour before ionizing radiation. Using scanning densitometry, the percentage inhibition relative to vehicle control is calculated, and the IC50 value is calculated as for the in vitro determinations.

Animal Study: [3]

Animal Models BALB/c nu/nu nude mice bearing LU1205 cells
Formulation
Dosages 10 μM
Administration
1

References

Chemical Information

Download KU-55933 SDF
Molecular Weight (MW) 395.49
Formula

C21H17NO3S2
CAS No. 587871-26-9
Synonyms N/A
Solubility (25°C)
  • DMSO 50 mg/mL
  • Water <1 mg/mL
  • Ethanol 13 mg/mL
Storage 2 years -20°CPowder
2 weeks4°Cin DMSO
6 months-80°Cin DMSO
Chemical Name 2-morpholino-6-(thianthren-1-yl)-4H-pyran-4-one
Molarity Calculator Dilution Calculator Molecular Weight Calculator

Research Area

Customer Reviews (3)


Click to enlarge 		Rating
Source Cancer Discovery, 2012, 2, 1048-1063. KU-55933 purchased from Selleck
Method Western Blot
Cell Lines HCC1937 cells
Concentrations 10 uM
Incubation Time 24 h
Results As expected, KU-55933 led to a decrease in autophosphorylation of ATM ( Fig. 5A , third and fourth lane of each panel), and prevented the increase in H2AX phosphorylation seen in response to ionizing radiation. However, KU-55933 did not prevent the NVP-BKM120–induced induction of γ-H2AX, which was robust both at baseline and in response to ionizing radiation ( Fig. 5A , last lane of each panel), suggesting that an alternative kinase, such as DNA-PK, phosphorylates H2AX in response to PI3K inhibition.

Click to enlarge 		Rating
Source J Immunol, 2012, 188, 2266-2275. KU-55933 purchased from Selleck
Method PD-beta assay
Cell Lines C22 cells
Concentrations 15 uM
Incubation Time 40 min
Results In contrast to controls exposed to DMSO carrier or inhibitors of p38 MAPK or Atm, when c22 cells were cultured with Nu7026, both USF-1 binding and 5’PDbeta2 repression were induced.

Click to enlarge 		Rating
Source J Biol Chem , 2011, 286, 8394-8404. KU-55933 purchased from Selleck
Method Cell Death Assay
Cell Lines HeLa cells
Concentrations 2 μM
Incubation Time 1 h
Results When the HeLa cells were pretreated with a specific ATM inhibitor KU55933, the ATM inhibition additively increased the etoposide-induced cell death in the PrxII knockdown cells.

Product Citations (11)

  • Systems Biology Approach Identifies the Kinase Csnk1a1 as a Regulator of the DNA Damage Response in Embryonic Stem Cells. [Jordi Carreras Puigvert, et al. Sci Signal 2013;6(259), ra5]

    PubMed: 23354688

  • Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress. [Singh K, et al. Autophagy 2012;8(2):236-51]

    PubMed: 22240589

  • DNA double-strand breaks relieve USF-mediated repression of Dβ2 germline transcription in developing thymocytes. [Stone JL, et al. J Immunol 2012;188(5):2266-75]

    PubMed: 22287717

  • Baculovirus infection induces a DNA damage response that is required for efficient viral replication. [Huang N, et al. J Virol 2011;85(23):12547-56]

    PubMed: 21917957

  • Peroxiredoxin II Restrains DNA Damage-induced Death in Cancer Cells by Positively Regulating JNK-dependent DNA Repair. [Lee KW, et al. J Biol Chem 2011;286(10), 8394-8404]

    PubMed: 21148313

  • The activation of the p53 pathway by the AMP mimetic AICAR is reduced by inhibitors of the ATM or mTOR kinases. [Zajkowicz A, et al. Mech Ageing Dev 2011;132(11-12), 543-551]

    PubMed: 21945951

  • Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer. [Mahajan K, et al. J Biol Chem 2012;287(26):22112-22]

    PubMed: 22566699

  • Heat shock protein 90α (Hsp90α) is phosphorylated in response to DNA damage and accumulates in repair foci. [Quanz M, et al. J Biol Chem 2012;287(12):8803-15]

    PubMed: 22270370

  • Radioprotective effect of hypothermia on cells-a multiparametric approach to delineate the mechanisms. [Dang L, et al. Int J Radiat Biol 2012;88(7):507-14]

    PubMed: 22449004

  • Jaceosidin, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. [Lee JG, et al. Food Chem Toxicol 2012;ahead of print]

    PubMed: 23274058

  • Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for a mouse model of BRCA1-related breast cancer. [Juvekar A, et al. Cancer Discov 2012;2(11):1048-63]

    PubMed: 22915751

Tech Support & FAQs

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.

Handling Instructions
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