Back to products

Browse products

MedKoo product information:

KU-55933

The ATM inhibitor, KU-55933, blocks the phosphorylation of Akt induced by insulin and insulin-like growth factor I in cancer cells that exhibit abnormal Akt activity. Moreover, KU-55933 inhibits cancer cell proliferation by inducing G(1) cell cycle arrest. It does so through the downregulation of the synthesis of cyclin D1, a protein known to be elevated in a variety of tumors. In addition, KU-55933 treatment during serum starvation triggers apoptosis in these cancer cells. Research results suggest that KU-55933 may be a novel chemotherapeutic agent targeting cancer resistant to traditional chemotherapy or immunotherapy due to aberrant activation of Akt. Furthermore, KU-55933 completely abrogates rapamycin-induced feedback activation of Akt. Combination of KU-55933 and rapamycin not only induces apoptosis, which is not seen in cancer cells treated only with rapamycin, but also shows better efficacy in inhibiting cancer cell proliferation than each drug alone. For detail see: http://www.ncbi.nlm.nih.gov/pubmed/20053781.

Current developer:    Merck

  1: Camins A, Pizarro JG, Alvira D, Gutierrez-Cuesta J, de la Torre AV, Folch J, Sureda FX, Verdaguer E, Junyent F, Jordán J, Ferrer I, Pallàs M. Activation of ataxia telangiectasia muted under experimental models and human Parkinson's disease. Cell Mol Life Sci. 2010 May 26. [Epub ahead of print] PubMed PMID: 20502937.

2: Pizarro JG, Folch J, de la Torre AV, Junyent F, Verdaguer E, Jordan J, Pallas

M, Camins A. ATM is involved in cell-cycle control through the regulation of retinoblastoma protein phosphorylation. J Cell Biochem. 2010 May;110(1):210-8. PubMed PMID: 20213763.

3: Rakkestad KE, Skaar I, Ansteinsson VE, Solhaug A, Holme JA, Pestka JJ, Samuelsen JT, Dahlman HJ, Hongslo JK, Becher R. DNA damage and DNA damage responses in THP-1 monocytes after exposure to spores of either Stachybotrys chartarum or Aspergillus versicolor or to T-2 toxin. Toxicol Sci. 2010 May;115(1):140-55. Epub 2010 Feb 11. PubMed PMID: 20150440.

4: Li Y, Yang DQ. The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther. 2010 Jan;9(1):113-25. Epub 2010 Jan 6. PubMed PMID: 20053781.

5: Chalmers AJ, Ruff EM, Martindale C, Lovegrove N, Short SC. Cytotoxic effects of temozolomide and radiation are additive- and schedule-dependent. Int J Radiat

Oncol Biol Phys. 2009 Dec 1;75(5):1511-9. PubMed PMID: 19931733.

6: Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, Chong WY, Hummersone M, Rigoreau L, Menear KA, O'Connor MJ, Povirk LF, van Meter

T, Valerie K. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther. 2009 Oct;8(10):2894-902. Epub 2009 Oct 6. PubMed PMID: 19808981; PubMed Central PMCID: PMC2761990.

7: Xue L, Yu D, Furusawa Y, Cao J, Okayasu R, Fan S. ATM-dependent hyper-radiosensitivity in mammalian cells irradiated by heavy ions. Int J Radiat

Oncol Biol Phys. 2009 Sep 1;75(1):235-43. PubMed PMID: 19695441.

8: Collaco RF, Bevington JM, Bhrigu V, Kalman-Maltese V, Trempe JP. Adeno-associated virus and adenovirus coinfection induces a cellular DNA damage and repair response via redundant phosphatidylinositol 3-like kinase pathways. Virology. 2009 Sep 15;392(1):24-33. Epub 2009 Jul 23. PubMed PMID: 19628243; PubMed Central PMCID: PMC2742906.

9: Wang Z, Wang M, Kar S, Carr BI. Involvement of ATM-mediated Chk1/2 and JNK kinase signaling activation in HKH40A-induced cell growth inhibition. J Cell Physiol. 2009 Oct;221(1):213-20. PubMed PMID: 19530246.

10: Kumari D, Somma V, Nakamura AJ, Bonner WM, D'Ambrosio E, Usdin K. The role of DNA damage response pathways in chromosome fragility in Fragile X syndrome. Nucleic Acids Res. 2009 Jul;37(13):4385-92. Epub 2009 May 21. PubMed PMID: 19465392; PubMed Central PMCID: PMC2715245.

11: Zhang YW, Jones TL, Martin SE, Caplen NJ, Pommier Y. Implication of checkpoint kinase-dependent up-regulation of ribonucleotide reductase R2 in DNA damage response. J Biol Chem. 2009 Jul 3;284(27):18085-95. Epub 2009 May 5. PubMed PMID: 19416980; PubMed Central PMCID: PMC2709352.

12: Pan Y, Yuan D, Zhang J, Xu P, Chen H, Shao C. Cadmium-induced adaptive response in cells of Chinese hamster ovary cell lines with varying DNA repair capacity. Radiat Res. 2009 Apr;171(4):446-53. PubMed PMID: 19397445.

13: Ivanov VN, Zhou H, Partridge MA, Hei TK. Inhibition of ataxia telangiectasia

mutated kinase activity enhances TRAIL-mediated apoptosis in human melanoma cells. Cancer Res. 2009 Apr 15;69(8):3510-9. Epub 2009 Apr 7. PubMed PMID: 19351839.

14: Ahmed KM, Nantajit D, Fan M, Murley JS, Grdina DJ, Li JJ. Coactivation of ATM/ERK/NF-kappaB in the low-dose radiation-induced radioadaptive response in human skin keratinocytes. Free Radic Biol Med. 2009 Jun 1;46(11):1543-50. Epub 2009 Mar 24. PubMed PMID: 19324081.

15: Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, Cippitelli M, Fionda C, Petrucci MT, Guarini A, Foà R, Santoni A. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood. 2009 Apr 9;113(15):3503-11. Epub 2008 Dec 19. PubMed PMID: 19098271.

16: Vitale I, Senovilla L, Galluzzi L, Criollo A, Vivet S, Castedo M, Kroemer G.

Chk1 inhibition activates p53 through p38 MAPK in tetraploid cancer cells. Cell Cycle. 2008 Jul 1;7(13):1956-61. PubMed PMID: 18642443.

17: Cheng WH, Muftic D, Muftuoglu M, Dawut L, Morris C, Helleday T, Shiloh Y, Bohr VA. WRN is required for ATM activation and the S-phase checkpoint in response to interstrand cross-link-induced DNA double-strand breaks. Mol Biol Cell. 2008 Sep;19(9):3923-33. Epub 2008 Jul 2. PubMed PMID: 18596239; PubMed Central PMCID: PMC2526706.

18: Perfettini JL, Nardacci R, Bourouba M, Subra F, Gros L, Séror C, Manic G, Rosselli F, Amendola A, Masdehors P, Chessa L, Novelli G, Ojcius DM, Siwicki JK,

Chechlinska M, Auclair C, Regueiro JR, de Thé H, Gougeon ML, Piacentini M, Kroemer G. Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. PLoS One. 2008 Jun 18;3(6):e2458. PubMed PMID: 18560558; PubMed Central PMCID: PMC2423469.

19: Halaby MJ, Hibma JC, He J, Yang DQ. ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells. Cell Signal. 2008 Aug;20(8):1555-63. Epub 2008 Apr 26. PubMed PMID: 18534819.

20: Yang XH, Shiotani B, Classon M, Zou L. Chk1 and Claspin potentiate PCNA ubiquitination. Genes Dev. 2008 May 1;22(9):1147-52. PubMed PMID: 18451105; PubMed Central PMCID: PMC2335311.

21: Crescenzi E, Palumbo G, de Boer J, Brady HJ. Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy. Clin Cancer Res. 2008 Mar 15;14(6):1877-87. PubMed PMID: 18347191.

22: Cruet-Hennequart S, Glynn MT, Murillo LS, Coyne S, Carty MP. Enhanced DNA-PK-mediated RPA2 hyperphosphorylation in DNA polymerase eta-deficient human cells treated with cisplatin and oxaliplatin. DNA Repair (Amst). 2008 Apr 2;7(4):582-96. Epub 2008 Mar 4. PubMed PMID: 18289945.

23: Yamauchi M, Oka Y, Yamamoto M, Niimura K, Uchida M, Kodama S, Watanabe M, Sekine I, Yamashita S, Suzuki K. Growth of persistent foci of DNA damage checkpoint factors is essential for amplification of G1 checkpoint signaling. DNA Repair (Amst). 2008 Mar 1;7(3):405-17. Epub 2008 Jan 8. PubMed PMID: 18248856.

24: You Z, Bailis JM, Johnson SA, Dilworth SM, Hunter T. Rapid activation of ATM

on DNA flanking double-strand breaks. Nat Cell Biol. 2007 Nov;9(11):1311-8. Epub

2007 Oct 21. PubMed PMID: 17952060.

25: Sun Y, Connors KE, Yang DQ. AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner. Mol Cell Biochem. 2007 Dec;306(1-2):239-45. Epub 2007 Sep 5. PubMed PMID: 17786544.

26: Eaton JS, Lin ZP, Sartorelli AC, Bonawitz ND, Shadel GS. Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis. J Clin Invest. 2007 Sep;117(9):2723-34. PubMed PMID: 17786248; PubMed Central PMCID: PMC1952633.

27: Kennedy RD, Chen CC, Stuckert P, Archila EM, De la Vega MA, Moreau LA, Shimamura A, D'Andrea AD. Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J Clin Invest. 2007 May;117(5):1440-9. Epub 2007 Apr 12. PubMed PMID: 17431503; PubMed Central PMCID: PMC1847538.

28: Hollick JJ, Rigoreau LJ, Cano-Soumillac C, Cockcroft X, Curtin NJ, Frigerio M, Golding BT, Guiard S, Hardcastle IR, Hickson I, Hummersone MG, Menear KA, Martin NM, Matthews I, Newell DR, Ord R, Richardson CJ, Smith GC, Griffin RJ. Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase

related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase. J Med Chem. 2007 Apr 19;50(8):1958-72. Epub 2007 Mar 20. PubMed PMID: 17371003.

29: Golding SE, Rosenberg E, Neill S, Dent P, Povirk LF, Valerie K. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res. 2007 Feb 1;67(3):1046-53. PubMed PMID: 17283137.

30: Ding J, Miao ZH, Meng LH, Geng MY. Emerging cancer therapeutic opportunities

target DNA-repair systems. Trends Pharmacol Sci. 2006 Jun;27(6):338-44. Epub 2006 May 11. Review. PubMed PMID: 16697054.

31: Moumen A, Masterson P, O'Connor MJ, Jackson SP. hnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage. Cell. 2005 Dec 16;123(6):1065-78. PubMed PMID: 16360036.

32: Cowell IG, Durkacz BW, Tilby MJ. Sensitization of breast carcinoma cells to ionizing radiation by small molecule inhibitors of DNA-dependent protein kinase and ataxia telangiectsia mutated. Biochem Pharmacol. 2005 Dec 19;71(1-2):13-20. Epub 2005 Nov 15. PubMed PMID: 16293233.

33: Khurdayan V, Bozzo J, Sorbera L. Chronicles in drug discovery. Drug News Perspect. 2005 Jun;18(5):332-6. PubMed PMID: 16193105.

34: Daniel R, Pomerantz RJ. ATM: HIV-1's Achilles heel? Nat Cell Biol. 2005 May;7(5):452-3. PubMed PMID: 15867928.

35: Lau A, Swinbank KM, Ahmed PS, Taylor DL, Jackson SP, Smith GC, O'Connor MJ. Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase. Nat Cell Biol. 2005 May;7(5):493-500. Epub 2005 Apr 17. PubMed PMID: 15834407.

36: Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NM, Orr AI, Reaper PM, Jackson SP, Curtin NJ, Smith GC. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004 Dec 15;64(24):9152-9. PubMed PMID: 15604286.