DOI QR코드

DOI QR Code

3D QSAR Studies of Mps1 (TTK) Kinase Inhibitors Based on CoMFA

Balasubramanian, Pavithra K.;Balupuri, Anand;Cho, Seung Joo

  • 투고 : 2016.05.05
  • 심사 : 2016.06.25
  • 발행 : 2016.06.30

초록

Monopolar spindle 1 (Mps1) is an attractive cancer target due to its high expression levels in a wide range of cancer cells. Mps1 is a dual specificity kinase. It plays an essential role in mitosis. The high expression od Mps1 was observed in various grades of breast cancers. In the current study, we have developed a CoMFA model of pyridazine derivatives as Mps1 kinase inhibitors. The developed CoMFA model ($q^2=0.797$; ONC=6; $r^2=0.992$) exhibited a good predictive ability. The model was then validated by Leave out five, progressive sampling and bootstrapping and found to be robust. The analysis of the CoMFA contour maps depicted favorable and unfavorable regions to enhance the activity. Bulky positive substitution at $R^3$ position and Negative substitution in $R^1$ position is favored could increase the activity. In contrast, bulky substitution in $R^1$ position is not favored. Our results can be used in designing a potent Mps1 (TTK) inhibitor.

키워드

CoMFA;Monopolar Spindle Kinase (Mps1);TTK Kinase;Pyridazine Derivatives;Kinase Inhibitors

참고문헌

  1. X. Liu and M. Winey, "The MPS1 family of protein kinases", Annu. Rev. Biochem., Vol. 81, pp. 561-585, 2012. https://doi.org/10.1146/annurev-biochem-061611-090435
  2. M. Winey, L. Goetsch, P. Baum, and B. Byers, "MPS1 and MPS2: novel yeast genes defining distinct steps of spindle pole body duplication", The Journal of Cell Biology, Vol.114, pp. 745-754, 1991. https://doi.org/10.1083/jcb.114.4.745
  3. A. M. Wengner, G. Siemeister, M. Koppitz, V. Schulze, D. Kosemund, U. Klar, D. Stoeckigt, R. Neuhaus, P. Lienau, B. Bader, S. Prechtl, M. Raschke, A.-L. Frisk, O. von Ahsen, M. Michels, B. Kreft, F. von Nussbaum, M. Brands, D. Mumberg, and K. Ziegelbauer, "Novel Mps1 kinase inhibitors with potent antitumor activity", Mol. Cancer Ther., Vol. 15, pp. 583-592, 2016. https://doi.org/10.1158/1535-7163.MCT-15-0500
  4. A. R. Schutz and M. Winey, "New alleles of the yeast MPS1 gene reveal multiple requirements in spindle pole body duplication", Mol. Biol. Cell, Vol. 9, pp. 759-774, 1998. https://doi.org/10.1091/mbc.9.4.759
  5. A. Abrieu, L. Magnaghi-Jaulin, J. A. Kahana, M. Peter, A. Castro, S. Vigneron, T. Lorca, D. W. Cleveland, and J.-C. Labbe, "Mps1 is a kinetochore-associated kinase essential for the vertebrate mitoticCheckpoint", Cell, Vol. 106, pp. 83-93, 2001. https://doi.org/10.1016/S0092-8674(01)00410-X
  6. V. M. Stucke, H. H. W. Sillje, L. Arnaud, and E. A. Nigg, "Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication", EMBO J., Vol. 21, pp. 1723-1732, 2002. https://doi.org/10.1093/emboj/21.7.1723
  7. H. A. Fisk, C. P Mattison, and M. Winey, "Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression", P. Natl. Acad. Sci, U.S.A., Vol. 100, pp. 14875-14880, 2003. https://doi.org/10.1073/pnas.2434156100
  8. K. Nihira, N. Taira, Y. Miki, and K. Yoshida, "TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress", Oncogene, Vol. 27, pp. 7285-7295, 2008. https://doi.org/10.1038/onc.2008.334
  9. J. Daniel, J. Coulter, J. H. Woo, K. Wilsbach, and E. Gabrielson, "High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells", P. Natl. Acad. Sci. U.S.A., Vol. 108, 5384-5389, 2011. https://doi.org/10.1073/pnas.1007645108
  10. M. T. Landi, T. Dracheva, M. Rotunno, J. D. Figueroa, H. Liu, A. Dasgupta, F. E. Mann, J. Fukuoka, M. Hames, A. W. Bergen, S. E. Murphy, P. Yang, A. C. Pesatori, D. Consonni, P. A. Bertazzi, S. Wacholder, J. H. Shih, N. E. Caporaso, and J. Jen, "Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival", Plos One, Vol. 3, pp. e1651, 2008. https://doi.org/10.1371/journal.pone.0001651
  11. G. Salvatore, T. C. Nappi, P. Salerno, Y. Jiang, C. Garbi, C. Ugolini, P. Miccoli, F. Basolo, M. D. Castellone, A. M. Cirafici, R. M. Melillo, A. Fusco, M. L. Bittner, and M. Santoro, "A cell proliferation and chromosomal instability signature in anaplastic thyroid Carcinoma", Cancer Res., Vol. 67, pp. 10148-10158, 2007. https://doi.org/10.1158/0008-5472.CAN-07-1887
  12. B. Yuan, Y. Xu, J.-H. Woo, Y. Wang, Y. K. Bae, D.-S. Yoon, R. P. Wersto, E. Tully, K. Wilsbach, and E. Gabrielson, "Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability", Clin. Cancer Res., Vol. 12, pp. 405-410, 2006. https://doi.org/10.1158/1078-0432.CCR-05-0903
  13. E Manchado, M Guillamot, and M. Malumbres, "Killing cells by targeting mitosis", Cell Death Differ., Vol. 19, pp. 369-377, 2012. https://doi.org/10.1038/cdd.2011.197
  14. K.-I. Kusakabe et al., "Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity", J. Med. Chem., Vol. 58, 1760-1775, 2015. https://doi.org/10.1021/jm501599u
  15. P. K. Balasubramanian, A. Balupuri, and S. J. Cho, "A CoMFA study of phenoxypyridine-based JNK3 inhibitors using various partial charge schemes", J. Chosun Natural Sci., Vol. 7, pp. 45-49, 2014. https://doi.org/10.13160/ricns.2014.7.1.45
  16. P. K. Balasubramanian and S. J. Cho, "HQSAR analysis on novel series of 1-(4-phenylpiperazin-1-yl-2-(1H-pyrazol-1-yl) ethanone derivatives targeting CCR1", J. Chosun Natural Sci., Vol. 6, pp. 163-169, 2013. https://doi.org/10.13160/ricns.2013.6.3.163
  17. A. Balupuri and S. J.Cho, "Exploration of the binding mode of indole derivatives as potent HIV-1 inhibitors using molecular docking simulations", J. Chosun Natural Sci., Vol. 6, pp. 138-142, 2013. https://doi.org/10.13160/ricns.2013.6.3.138
  18. P. K. Balasubramanian, A. Balupuri, and S. J. Cho, "3D QSAR study on pyrrolopyrimidines-based derivatives as LIM2 kinase inhibitors", J. Chosun Natural Sci., Vol. 8, pp. 285-292, 2015. https://doi.org/10.13160/ricns.2015.8.4.285
  19. S. J. Cho, "The importance of halogen bonding: A tutorial", J. Chosun Natural Sci., Vol. 5, pp. 195-197, 2012. https://doi.org/10.13160/ricns.2012.5.3.195
  20. SYBYLx2.1, Tripos International, 1699 South Hanley Road, St. Louis, Missouri, 63144, USA.
  21. R. D. Cramer, D. E. Patterson, and J. D. Bunce, "Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins", J. Am. Chem. Soc., Vol. 110, pp. 5959-5967,1988. https://doi.org/10.1021/ja00226a005

과제정보

연구 과제 주관 기관 : National Research Foundation of Korea