Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells

  • Park, Young Hwan (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Hyun Woo (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Hyuk Soon (Department of Immunology, College of Medicine, Konkuk University) ;
  • Nam, Seung Taek (Department of Immunology, College of Medicine, Konkuk University) ;
  • Lee, Dajeong (Department of Immunology, College of Medicine, Konkuk University) ;
  • Lee, Min Bum (Department of Immunology, College of Medicine, Konkuk University) ;
  • Min, Keun Young (Department of Immunology, College of Medicine, Konkuk University) ;
  • Koo, Jimo (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Su Jeong (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Young Mi (College of Pharmacy, Duksung Women's University) ;
  • Kim, Hyung Sik (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Choi, Wahn Soo (Department of Immunology, College of Medicine, Konkuk University)
  • Received : 2018.08.01
  • Accepted : 2018.08.21
  • Published : 2019.05.01
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Abstract

Mast cells are the most prominent effector cells of Type 1 hypersensitivity immune responses. CYC116 [4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl] pyrimidin-2-amine] is under development to be used as an anti-cancer drug, but the inhibitory effects of CYC116 on the activation of mast cells and related allergy diseases have not reported as of yet. In this study, we demonstrated, for the first time, that CYC116 inhibited the degranulation of mast cells by antigen stimulation ($IC_{50}$, ${\sim}1.42{\mu}M$). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-${\alpha}$ ($IC_{50}$, ${\sim}1.10{\mu}M$), and IL-6 ($IC_{50}$, ${\sim}1.24{\mu}M$). CYC116 inhibited the mast cell-mediated allergic responses, passive cutaneous anaphylaxis (ED50, ~22.5 mg/kg), and passive systemic anaphylaxis in a dose-dependent manner in laboratory experiments performed on mice. Specifically, CYC116 inhibited the activity of Fyn in mast cells and inhibited the activation of Syk and Syk-dependent signaling proteins including LAT, $PLC{\gamma}$, Akt, and MAP kinases. Our results suggest that CYC116 could be used as an alternative therapeutic medication for mast cell-mediated allergic disorders, such as atopic dermatitis and allergic rhinitis.

Keywords

References

  1. Baba, Y., Hayashi, K., Fujii, Y., Mizushima, A., Watarai, H., Wakamori, M., Numaga, T., Mori, Y., Iino, M., Hikida, M. and Kurosaki, T. (2006) Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. Proc. Natl. Acad. Sci. U.S.A. 103, 16704-16709. https://doi.org/10.1073/pnas.0608358103
  2. Beuchet, P., Varache-Lembege, M., Neveu, A., Leger, J. M., Vercauteren, J., Larrouture, S., Deffieux, G. and Nuhrich, A. (1999) New 2-sulfonamidothiazoles substituted at C-4: synthesis of polyoxygenated aryl derivatives and in vitro evaluation of antifungal activity. Eur. J. Med. Chem. 34, 773-779. https://doi.org/10.1016/S0223-5234(99)00215-9
  3. Bradding, P., Roberts, J. A., Britten, K. M., Montefort, S., Djukanovic, R., Mueller, R., Heusser, C. H., Howarth, P. H. and Holgate, S.T. (1994) Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am. J. Respir. Cell Mol. Biol. 10, 471-480. https://doi.org/10.1165/ajrcmb.10.5.8179909
  4. Carmena, M. and Earnshaw, W. C. (2003) The cellular geography of aurora kinases. Nat. Rev. Mol. Cell. Biol. 4, 842-854. https://doi.org/10.1038/nrm1245
  5. Das, J., Furch, J. A., Liu, C., Moquin, R. V., Lin, J., Spergel, S. H., Mc-Intyre, K. W., Shuster, D. J., O'Day, K. D., Penhallow, B. and Hung, C. Y. (2006) Discovery and SAR of 2-amino-5-(thioaryl) thiazoles as potent and selective Itk inhibitors. Bioorg. Med. Chem. Lett. 16, 3706-3712. https://doi.org/10.1016/j.bmcl.2006.04.060
  6. Fu, J., Bian, M., Jiang, Q. and Zhang, C. (2007) Roles of Aurora Kinases in Mitosis and Tumorigenesis. Mol. Cancer Res. 5, 1-10. https://doi.org/10.1158/1541-7786.MCR-06-0208
  7. Furumoto, Y., Nunomura, S., Terada, T., Rivera, J. and Ra, C. (2004) The FcepsilonRIBeta immunoreceptor tyrosine-based activation motif exerts inhibitory control on MAPK and IkappaB kinase phosphorylation and mast cell cytokine production. J. Biol. Chem. 279, 49177-49187. https://doi.org/10.1074/jbc.M404730200
  8. Furumoto, Y., Brooks, S., Olivera, A., Takagi, Y., Miyagishi, M., Taira, K., Casellas, R., Beaven, M. A., Gilfillan, A. M. and Rivera, J. (2006) Cutting edge: lentiviral short hairpin RNA silencing of PTEN in human mast cells reveals constitutive signals that promote cytokine secretion and cell survival. J. Immunol. 176, 5167-5171. https://doi.org/10.4049/jimmunol.176.9.5167
  9. Galli, S. J., Nakae, S. and Tsai, M. (2005) Mast cells in the development of adaptive immune responses. Nat. Immunol. 6, 135-142. https://doi.org/10.1038/ni1158
  10. Gilfillan, A. M. and Tkaczyk, C. (2006) Integrated signaling pathways for mast-cell activation. Nat. Rev. Immunol. 6, 218-230. https://doi.org/10.1038/nri1782
  11. Gilfillan, A. M. and Rivera, J. (2009) The tyrosine kinase network regulating mast cell activation. Immunol. Rev. 228, 149-169. https://doi.org/10.1111/j.1600-065X.2008.00742.x
  12. Goblyos, A., Santiago, S. N., Pietra, D., Mulder-Krieger, T., von Frijtag, Drabbe, Kunzel, J., Brussee, J. and Ijzerman, A. P. (2005) Synthesis and biological evaluation of 2-aminothiazoles and their derivatives on human adenosine receptors. Lack of effect of 2-aminothiazoles as allosteric enhancers. Bioorg. Med. Chem. 13, 2079-2087. https://doi.org/10.1016/j.bmc.2005.01.006
  13. Griffiths, G., Scaerou, F., Midgley, C., McClue, S., Tosh, C., Jackson, W., MacCallum, D., Wang, S., Fischer, P., Glover, D. and Zheleva, D. (2008) Anti-tumor activity of CYC116, a novel small molecule inhibitor of aurora kinases and VEGFR2. Cancer Res. 49, 5644 (Abstract).
  14. Grimbaldeston, M. A., Metz, M., Yu, M., Tsai, M. and Galli, S. J. (2006) Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune response. Curr. Opin. Immunol. 18, 751-760. https://doi.org/10.1016/j.coi.2006.09.011
  15. Hajduch, M., Vydra, D., Dzubak, P., Dziechciarkova, M., Stuart, I. and Zheleva, D. (2008) In vivo mode of action of CYC116, a novel small molecule inhibitor of aurora kinases and VEGFR2. Cancer Res. 49, 5645 (Abstract).
  16. Hallgren, J. and Gurish, M. F. (2007) Pathways of murine mast cell development and trafficking: tracking the roots and routes of the mast cell. Immunol. Rev. 217, 8-18. https://doi.org/10.1111/j.1600-065X.2007.00502.x
  17. Hang, P. C. and Honek, J. F. (2005) Electronic structure calculations on the thiazole-containing antibiotic thiostrepton: molecular mechanics, semi-empirical and ab initio analyses. Bioorg. Med. Chem. Lett. 15, 1471-1474. https://doi.org/10.1016/j.bmcl.2004.12.076
  18. Ito, R., Takahashi, T., Katano, I., Kawai, K., Kamisako, T., Ogura, T., Ida-Tanaka, M., Suemizu, H., Nunomura, S., Ra, C., Mori, A., Aiso, S. and Ito, M. (2013) Establishment of a human allergy model using human IL-3/GM-CSF-transgenic NOG mice. J. Immunol. 191, 2890-2899. https://doi.org/10.4049/jimmunol.1203543
  19. Kitakura, J., Asai, K., Maeda-Yamamoto, M., Kawakami, Y., Kikkawa, U., Kawakami, T. (2000) Akt-dependent cytokine production in mast cells. J. Exp. Med. 192, 729-740. https://doi.org/10.1084/jem.192.5.729
  20. Lee, J. H., Kim, Y. M., Kim, N. W., Kim, J. W., Her, E., Kim, B. K., Kim, J. H., Ryu, S. H., Park, J. W. and Seo, D. W. (2006) Phospholipase D2 acts as an essential adaptor protein in the activation of Syk in antigen-stimulated mast cells. Blood 108, 956-964. https://doi.org/10.1182/blood-2005-10-009159
  21. Luik, R. M., Wu, M. M., Buchanan, J. and Lewis, R. S. (2006) The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J. Cell Biol. 174, 815-825. https://doi.org/10.1083/jcb.200604015
  22. Maier, J. V., Brema, S., Tuckermann, J., Herzer, U., Klein, M., Stassen, M., Moorthy, A. and Cato, A. C. (2007) Dual specificity phosphatase 1 knockout mice show enhanced susceptibility to anaphylaxis but are sensitive to glucocorticoids. Mol. Endocrinol. 21, 2663-2671. https://doi.org/10.1210/me.2007-0067
  23. Metcalfe, D. D., Baram, D. and Mekori, Y. A. (1997) Mast cells. Physiol. Rev. 77, 1033-1079. https://doi.org/10.1152/physrev.1997.77.4.1033
  24. Nam, S. T., Kim, H. W., Kim, H. S., Park, Y.H., Lee, D., Lee, M. B., Min, K. Y., Kim, Y. M and Choi, W. S. (2018) Furaltadone suppresses IgE-mediated allergic response through the inhibition of Lyn/Syk pathway in mast cells. Eur. J. Pharmacol. 828, 119-125 https://doi.org/10.1016/j.ejphar.2018.03.035
  25. Ozdemir, C., Akdis, M. and Akdis, C. A. (2010) T-cell response to allergens. Chem. Immunol. Allergy 95, 22-44. https://doi.org/10.1159/000315936
  26. Parravicini, V., Gadina, M., Kovarova, M., Odom, S., Gonzalez-Espinosa, C., Furumoto, Y., Saitoh, S., Samelson, L. E., O'Shea, J. J. and Rivera, J. (2002) Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nat. Immunol. 3, 741-748. https://doi.org/10.1038/ni817
  27. Pawankar, R., Canonica, G. W., Holgate, G. T., Lockey, R. F., Blaiss, M. S. (2013) WAO White Book on Allergy: Update 2013, p. 11. World Allergy Organization, Milwaukee. Available from: http://www.worldallergy.org/UserFiles/file/WhiteBook2-2013-v8.pdf/.
  28. Portnoy, J. M. and Dinakar, C. (2004) Review of cetirizine hydrochloride for the treatment of allergic disorders. Expert. Opin. Pharmacother. 5, 125-135. https://doi.org/10.1517/14656566.5.1.125
  29. Rivera, J. and Gilfillan, A. M. (2006) Molecular regulation of mast cell activation. J. Allergy Clin. Immunol. 117, 1214-1225. https://doi.org/10.1016/j.jaci.2006.04.015
  30. Siebenhaar, F., Redegeld, F. A., Bischoff, S. C., Gibbs, B. F. and Maurer, M. (2018) Mast cells as drivers of disease and therapeutic targets. Trends Immunol. 39, 151-162. https://doi.org/10.1016/j.it.2017.10.005
  31. Siraganian, R. P., de Castro, R. O., Barbu, E. A. and Zhang, J. (2010) Mast cell signaling: the role of protein tyrosine kinase Syk, its activation and screening methods for new pathway participants. FEBS Lett. 584, 4933-4940. https://doi.org/10.1016/j.febslet.2010.08.006
  32. Theoharides, T. C., Kempuraj, D., Tagen, M., Conti, P. and Kalogeromitros, D. (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol. Rev. 217, 65-78. https://doi.org/10.1111/j.1600-065X.2007.00519.x
  33. Theoharides, T. C., Alysandratos, K. D., Angelidou, A., Delivanis, D. A., Sismanopoulos, N., Zhang, B., Asadi, S., Vasiadi, M., Weng, Z., Miniati, A. and Kalogeromitros, D. (2012) Mast cell and inflammation. Biochim. Biophys. Acta 1822, 21-33. https://doi.org/10.1016/j.bbadis.2010.12.014
  34. Wang, S., Midgley, C. A., Scaerou, F., Grabarek, J. B., Griffiths, G., Jackson, W., Kontopidis, G., McClue, S. J., McInnes, C., Meades, C., Mezna, M., Plater, A., Stuart, I., Thomas, M. P., Wood, G., Clarke, R. G., Blake, D. G., Zheleva, D. I., Lane, D. P., Jackson, R. C., Glover, D. M. and Fischer, P. M. (2010) Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors. J. Med. Chem. 53, 4367-4378. https://doi.org/10.1021/jm901913s
  35. Zhang, C., Baumgartner, R. A., Yamada, K. and Beaven, M. A. (1997) Mitogen-activated Protein (MAP) kinase regulates production of tumor necrosis factor-${\alpha}$ and release of arachidonic acid in mast cells indications of communication between p38 and p42 Map kinases. J. Biol. Chem. 272, 13397-13402. https://doi.org/10.1074/jbc.272.20.13397

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