YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Inhibitory Effects of Dithiolo-thione Derivative SWU-20009 on Akt Activity

Dithiolo-thione 계열 유도체 SWU-20009의 Akt활성 저해 효과

  • 고종희 (일동제약주식회사 중앙연구소) ;
  • 연승우 (일동제약주식회사 중앙연구소) ;
  • 이홍섭 (일동제약주식회사 중앙연구소) ;
  • 김태용 (일동제약주식회사 중앙연구소) ;
  • 노동윤 (서울여자대학교 화학과) ;
  • 신경순 (서울여자대학교 화학과) ;
  • 홍순광 (명지대학교 생물학과) ;
  • 강상순 (충북대학교 과학교육과)
  • Published : 2004.04.01
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Abstract

Akt (or Protein Kinase B; PKB) is a serine/threonine kinase and is activated by phosphoinositide 3-kinase (PI3K) pathway. Recent evidence indicates that the abnormal activities or expression of Akt is closely associated with cancer, diabetes and neuro-degenerative diseases. These findings mean that Akt is likely to be a new therapeutic target for the treatment of disease. Here, we screened the effects of dithiolo-dithione derivatives such as SWU-20004, SWU-20009 and SWU-20025 on Akt activities. Among these compounds, only SWU-20009 (2-Thioxo-[1,3]dithiolo[4,5- $\beta$][1,4]dithiine-5,6-dicarboxylic acid dimethyl ester) inhibited the growth of KATOIII cell at micromolar range of concentration. Further investigation also revealed that SWU-20009 inhibited cellular Akt activity and induced apoptotic cell death.

Keywords

References

  1. Hanslam, R. J., Kodle, H. B. and Hemmings, B. A. : Pleckstrin domain homology. Nature 363, 309 (1993)
  2. Shaw, G. : The pleckstrin homology domain : an intriguing multifunctional protein module. Bioessays 18, 35 (1996) https://doi.org/10.1002/bies.950180109
  3. Lewis, C. C. : The phosphoinositide 3-kinase pathwawy. Science 296, 1655 (2002) https://doi.org/10.1126/science.296.5573.1655
  4. Reuveni, H., Linvnah, N., Geiger, T., Klein, S., Ohne, O., Cohen, I., Benhar, M., Gellerman, G. and Levitski, A. : Toward A PKB inhibitor : Modification of a selective PKA inhibitor by rational design. Biochemistry 41, 10304 (2002) https://doi.org/10.1021/bi0202530
  5. Staal, S. P. and Hartley, J. W. : Thymic lymphoma induction by the AKT8 murine retrovirus. J. Exp. Med. 167, 1259 (1988) https://doi.org/10.1084/jem.167.3.1259
  6. Ozes, O. N., Myyom L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M. and Donner, D. B. : NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401, 82 (1999) https://doi.org/10.1038/43466
  7. Romashkova, J. A. and Makarov, S. S. : NF-kappaB is a target of AKT in anti-apoptotic PDGF signaling. Nature 401, 86 (1999) https://doi.org/10.1038/43474
  8. Kwon, T. G., Kwon D. Y., Chun, J. S., Kim, J. H. and Kang, S. S. : Akt protein kinase inhibits Racl-GTP binding through phosphorylation at serine 71 of Rac1. J. Biol. Chem. 275. 423 (2000)
  9. Tang, D., Okada, H., Ruland, J., Liu, L., Stambolic, V., Mak, T. W. and Ingram, A. J. : Akt is activated in response to an apoptotic signal. J. Biol. Chem. 276, 30461 (2001) https://doi.org/10.1074/jbc.M102045200
  10. Frame, S. and Cohen, P. : GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1 (2001) https://doi.org/10.1042/0264-6021:3590001
  11. Roskoski, R. Jr. : STO-571 : an anitcancer protein-tyrosine kinase inhibitor. Biochem. Biophys Res. Commun. 309, 709 (2003)