통합자연과학논문집 (Journal of Integrative Natural Science)

조선대학교 기초과학연구원 (The Basic Science Institute Chosun University)
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HQSAR Study on Substituted 1H-Pyrazolo[3,4-b]pyridines Derivatives as FGFR Kinase Antagonists

  • Bhujbal, Swapnil P. (Department of Biomedical Sciences, College of Medicine, Chosun University) ;
  • Balasubramanian, Pavithra K. (Department of Biomedical Sciences, College of Medicine, Chosun University) ;
  • Keretsu, Seketoulie (Department of Biomedical Sciences, College of Medicine, Chosun University) ;
  • Cho, Seung Joo (Department of Biomedical Sciences, College of Medicine, Chosun University)
  • 투고 : 2017.05.01
  • 심사 : 2017.06.25
  • 발행 : 2017.06.30
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초록

Fibroblast growth factor receptor (FGFR) belongs to the family of receptor tyrosine kinase. They play important roles in cell proliferation, differentiation, development, migration, survival, wound healing, haematopoiesis and tumorigenesis. FGFRs are reported to cause several types of cancers in humans which make it an important drug target. In the current study, HQSAR analysis was performed on a series of recently reported 1H-Pyrazolo [3,4-b]pyridine derivatives as FGFR antagonists. The model was developed with Atom (A) and bond (B) connection (C), chirality (Ch), hydrogen (H) and donor/acceptor (DA) parameters and with different set of atom counts to improve the model. A reasonable HQSAR model ($q^2=0.701$, SDEP=0.654, NOC=5, $r^2=0.926$, SEE=0.325, BHL=71) was generated which showed good predictive ability. The contribution map depicted the atom contribution in inhibitory effect. A contribution map for the most active compound (compound 24) indicated that hydrogen and nitrogen atoms in the side chains of ring B as well as hydrogen atoms in the side chain of ring C and the nitrogen atom in the ring D contributed positively to the activity in inhibitory effect whereas, the lowest active compound (compound 04) showed negative contribution to inhibitory effect. Thus results of our study can provide insights in the designing potent and selective FGFR kinase inhibitors.

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참고문헌

  1. A. D. Luca, D. Frezzetti, M. Gallo, and N. Normanno, "FGFR-targeted therapeutics for the treatment of breast cancer", Expert Opin. Investig. Drugs, Vol. 26, pp. 303-311, 2017. https://doi.org/10.1080/13543784.2017.1287173
  2. I. S. Babina and N. C. Turner, "Advances and challenges in targeting FGFR signalling in cancer", Nat. Rev. Cancer, Vol. 17, pp. 318-332, 2017. https://doi.org/10.1038/nrc.2017.8
  3. K. H. Tiong, L. Y. Mah, and C.-O. Leong, "Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers", Apoptosis, Vol. 18, pp. 1447-1468, 2013. https://doi.org/10.1007/s10495-013-0886-7
  4. M. Touat, E. Ileana, S. Postel-Vinay, F. Andre, and J. C. Soria, "Targeting FGFR signaling in cancer", Clin. Cancer Res., Vol. 21, pp. 2684-2694, 2015. https://doi.org/10.1158/1078-0432.CCR-14-2329
  5. E. M. Haugsten, A. Wiedlocha, S. Olsnes, and J. Wesche, "Roles of fibroblast growth factor receptors in carcinogenesis", Mol. Cancer Res., Vol. 8, pp. 1439-1452, 2010. https://doi.org/10.1158/1541-7786.MCR-10-0168
  6. H. Greulich and P. M. Pollock, "Targeting mutant fibroblast growth factor receptors in cancer", Trends Mol. Med., Vol. 17, pp. 283-292, 2013.
  7. H. K. Ho, A. H. Yeo, T. S. Kang, and B. T. Chua, "Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations", Drug Discov. Today, Vol. 9, pp. 51-62, 2014.
  8. J. M. Siegfried, M. Farooqui, N. J. Rothenberger, S. Dacic, and L. P. Stabile, "Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer", Oncotarget, Vol. 8, pp. 24063-24076, 2017.
  9. E. M. Haugsten, A. Wiedlocha, S. Olsnes, and J. Wesche, "Roles of fibroblast growth factor receptors in carcinogenesis", Mol. Cancer Res., Vol. 8, pp. 1439-1452, 2010. https://doi.org/10.1158/1541-7786.MCR-10-0168
  10. Y. J. Shi, J. Y. Tsang, Y. B. Ni, S. K. Chan, K. F. Chan and G. M. Tse, "FGFR1 is an adverse outcome indicator for luminal A breast cancers", Oncotarget, Vol. 7, pp. 5063-5073, 2016. https://doi.org/10.18632/oncotarget.6563
  11. N. Turner and R. Grose, "Fibroblast growth factor signalling: from development to cancer", Nat. Rev. Cancer, Vol. 10, pp. 116-129, 2010. https://doi.org/10.1038/nrc2780
  12. N. Brooks, E. Kilgour, and P. D. Smith, "Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer", Clin. Cancer Res., Vol. 18, pp. 1855-1862, 2012. https://doi.org/10.1158/1078-0432.CCR-11-0699
  13. S. Lemieux and M. K. Hadden, "Targeting the fibroblast growth factor receptors for the treatment of cancer", Anti-Cancer Agents Med. Chem., Vol. 13, pp. 748-761, 2013. https://doi.org/10.2174/18715206113139990080
  14. R. Porta, R. Borea, A. Coelho, S. Khan, A. Araujo, P. Reclusa, T. Franchina, N. V. D. Steen, P. V. Dam, J. Ferri, R. Sirera, A. Naing, D. Hong, and C. Rolfo, "FGFR a promising druggable target in cancer: Molecular biology and new drugs", Crit. Rev. Oncol. Hematol., Vol. 113, pp. 256-267, 2017. https://doi.org/10.1016/j.critrevonc.2017.02.018
  15. H. Izzedine, S. Ederhy, F. Goldwasser, J. C. Soria, G. Milano, A. Cohen, D. Khayat, and J. P. Spano, "Management of hypertension in angiogenesis inhibitor-treated patients", Ann. Oncol., Vol. 20, pp. 807-815, 2009. https://doi.org/10.1093/annonc/mdn713
  16. S. Ricciardi, S. Tomao, and F. de Marinis, "Toxicity of targeted therapy in non-small-cell lung cancer management", Clin. Lung Cancer, Vol. 10, pp. 28-35, 2009. https://doi.org/10.3816/CLC.2009.n.004
  17. B. Zhao, Y. Li, P. Xu, Y. Dai, C. Luo, Y. Sun, J. Ai, M. Geng, and W. Duan, "Discovery of substituted 1H-Pyrazolo[3,4-b]pyridine derivatives as potent and selective FGFR kinase inhibitors", ACS Med. Chem. Lett., Vol. 7, pp. 629-634, 2016. https://doi.org/10.1021/acsmedchemlett.6b00066
  18. M. Clark, R. D. Cramer III, and N. V. Opdenbosch, "Validation of the General Purpose Tripos 5.2 Force Field", J. Comput. Chem., Vol. 10, pp. 982-1012, 1989. https://doi.org/10.1002/jcc.540100804
  19. R. Kumar, B. Langstrom, and T. Darreh-Shori, "Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization", Sci. Rep., Vol. 6, p. 31247, 2016. https://doi.org/10.1038/srep31247
  20. A. Balupuri, P. K. Balasubramanian, and S. J. Cho, "A CoMFA study of glycogen synthase kinase 3 inhibitors", J. Chosun Natural Sci., Vol. 8, pp. 40-47, 2015. https://doi.org/10.13160/ricns.2015.8.1.40
  21. A. Balupuri, P. K. Balasubramanian, and S. J. Cho, "A CoMFA study of quinazoline-based anticancer agents", J. Chosun Natural Sci., Vol. 8, pp. 214-220, 2015. https://doi.org/10.13160/ricns.2015.8.3.214
  22. A. Balupuri, P. K. Balasubramanian, and S. J. Cho, "Comparative molecular field analysis of pyrrolopyrimidinesas LRRK2 kinase inhibitors", J. Chosun Natural Sci., Vol. 9, pp. 1-9, 2016. https://doi.org/10.13160/ricns.2016.9.1.1
  23. 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

피인용 문헌

  1. Hologram Quantitative Structure-Activity Relationships Study of N-Phenyl-N'-{4-(4-quinolyloxy)phenyl} Urea Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors vol.10, pp.3, 2017, https://doi.org/10.13160/ricns.2017.10.3.141