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Discovery of Novel and Potent Cdc25 Phosphatase Inhibitors Based on the Structure-Based De Novo Design

  • Park, Hwang-Seo (Department of Bioscience and Biotechnology, Sejong University) ;
  • Jung, Suk-Kyeong (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Bahn, Young-Jae (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Jeong, Dae-Gwin (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Ryu, Seong-Eon (Department of Bio-engineering, Hanyang University) ;
  • Kim, Seung-Jun (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
  • Published : 2009.06.20

Abstract

Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy due to the correlation of their overexpression with a wide variety of cancers. We have been able to identify five novel Cdc25 phosphatase inhibitors with micromolar activity by means of a structure-based de novo design method with a known inhibitor scaffold. Because the newly discovered inhibitors are structurally diverse and have desirable physicochemical properties as a drug candidate, they deserve further investigation as anticancer drugs. The differences in binding modes of the identified inhibitors in the active sites of Cdc25A and B are addressed in detail.

Keywords

References

  1. Kristjansdottir, K.; Rudolph, J. Chem. Biol. 2004, 11, 1043. https://doi.org/10.1016/j.chembiol.2004.07.007
  2. Rudolph, J. Biochemistry 2007, 46, 3595. https://doi.org/10.1021/bi700026j
  3. Galaktionov, K.; Lee, A. K.; Eckstein, J.; Draetta, G.; Meckler, J.; Loda, M.; Beach, D. Science 1995, 269, 1575. https://doi.org/10.1126/science.7667636
  4. Takemara, I.; Yamamoto, H.; Sekimoto, M.; Ohue, M.; Noura, S.; Miyake, Y.; Matsumoto, T.; Aihara, T.; Tomita, N.; Tamaki, Y.; Sakita, I.; Kikkawa, N.; Matsuura, N.; Shiozaki, H.; Monden, M. Cancer Res. 2000, 60, 3043.
  5. Ngan, E. S. W.; Hashimoto, Y.; Ma, Z.-Q.; Tsai, M. J.; Tsai, S. Y. Oncogene 2003, 22, 734. https://doi.org/10.1038/sj.onc.1206121
  6. Boutros, R.; Dozier, C.; Ducommun, B. Curr. Opin. Cell Biol. 2006, 18, 185. https://doi.org/10.1016/j.ceb.2006.02.003
  7. Fauman, E. B.; Cogswell, J. P.; Lovejoy, B.; Rocque, W. J.; Holmes, W.; Montana, V. G.; Piwnica-Worms, H.; Rink, M. J.; Saper, M. A. Cell 1998, 93, 617. https://doi.org/10.1016/S0092-8674(00)81190-3
  8. Reynolds, R. A.; Yem, A. W.; Wolfe, C. L.; Deibel, M. R.; Chidester, C. G.; Watenpaugh, K. D. J. Mol. Biol. 1999, 293, 559. https://doi.org/10.1006/jmbi.1999.3168
  9. Contour-Galcéra, M.-O.; Sidhu, A.; Prévost, G.; Bigg, D.; Ducommun, B. Pharmcol. Ther. 2007, 115, 1. https://doi.org/10.1016/j.pharmthera.2007.03.009
  10. Ham, S. W.; Carr, B. I. Drug Des. Rev. 2004, 1, 123.
  11. Lazo, J. S.; Aslan, D. C.; Southwick, E. C.; Cooley, K. A.; Ducruet, A. P.; Joo, B.; Vogt, A.; Wipf, P. J. Med. Chem. 2001, 44, 4042. https://doi.org/10.1021/jm0102046
  12. Sohn, J.; Kiburz, B.; Li, Z.; Deng, L.; Safi, A.; Pirrung, M. C.; Rudolph, J. J. Med. Chem. 2003, 46, 2580. https://doi.org/10.1021/jm0300835
  13. Brault, L.; Denance, M.; Banaszak, E.; Maadidi, S. E.; Battaglia, E.; Bagrel, D.; Samadi, M. Eur. J. Med. Chem. 2007, 42, 243. https://doi.org/10.1016/j.ejmech.2006.09.014
  14. Huang, W.; Li, J.; Zhang, W.; Zhou, Y.; Xie, C.; Luo, Y.; Li, Y.; Wang, J.; Li, J.; Lu, W. Bioorg. Med. Chem. Lett. 2006, 16, 1905. https://doi.org/10.1016/j.bmcl.2005.12.080
  15. Lazo, J. S.; Nemoto, K.; Pestell, K. E.; Cooley, K.; Southwick, E. C.; Mitchell, D. A.; Furey, W.; Gussio, R.; Zaharevitz, D.W.; Joo, B.; Wipf, P. Mol. Pharmacol. 2002, 61, 720. https://doi.org/10.1124/mol.61.4.720
  16. Lavecchia, A.; Cosconati, S.; Limongelli, V.; Novellino, E. Chem. Med. Chem 2006, 1, 540. https://doi.org/10.1002/cmdc.200500092
  17. Park, H.; Carr, B. I.; Li, M.; Ham, S. W. Bioorg. Med. Chem. Lett. 2007, 17, 2351. https://doi.org/10.1016/j.bmcl.2006.12.046
  18. Park, H.; Bahn, Y. J.; Jung, S.-K.; Jeong, D. G.; Lee, S.-H.; Seo, I.; Yoon, T.-S.; Kim, S. J.; Ryu, S. E. J. Med. Chem. 2008, 51, 5533. https://doi.org/10.1021/jm701157g
  19. Shoichet, B. K.; Leach, A. R.; Kuntz, I. D. Proteins 1999, 34, 4. https://doi.org/10.1002/(SICI)1097-0134(19990101)34:1<4::AID-PROT2>3.0.CO;2-6
  20. Wang, R.; Gao, Y.; Lai, L. J. Mol. Model. 2000, 6, 498. https://doi.org/10.1007/s0089400060498
  21. Wang, R.; Liu, L.; Lai, L. J. Mol. Model. 1998, 6, 379.
  22. Gasteiger, J.; Marsili, M. Tetrahedron 1980, 36, 3219. https://doi.org/10.1016/0040-4020(80)80168-2
  23. Kang, H.; Choi, H.; Park, H. J. Chem. Inf. Model. 2007, 47, 509. https://doi.org/10.1021/ci600453b
  24. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. J. Comput. Chem. 1998, 19, 1639. https://doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B
  25. Lee, W.; Park, H.; Lee, S. Bull. Korean Chem. Soc. 2008, 29, 363. https://doi.org/10.5012/bkcs.2008.29.2.363
  26. Park, J.-H.; Ko, S.; Park, H. Bull. Korean Chem. Soc. 2008, 29, 921. https://doi.org/10.5012/bkcs.2008.29.5.921
  27. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug. Delivery. Rev. 1997, 23, 3. https://doi.org/10.1016/S0169-409X(96)00423-1
  28. Tamura, K.; Southwick, E. C.; Kerns, J.; Rosi, K.; Carr, B. I.; Wilcox, C.; Lazo, J. S. Cancer Res. 2000 60, 1317.
  29. Osada, S.; Osada, K.; Carr, B. I. J. Mol. Biol. 2001, 314, 765. https://doi.org/10.1006/jmbi.2001.5171

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