The search for potential inhibitors of protein kinase Pim-1 among new amides of 1,2,4-triazolo[4,3-a]pyridine-3-metanamin with the 1,2,4-oxadiazol cycle in position 7 and 8

Authors

  • V. R. Karpina National University of Pharmacy, Ukraine
  • S. M. Kovalenko V. N. Karazin Kharkiv National University, Ukraine
  • O. V. Zaremba V. N. Karazin Kharkiv National University, Ukraine
  • O. V. Silin National University of Pharmacy, Ukraine
  • V. V. Ivanov V. N. Karazin Kharkiv National University, Ukraine
  • S. S. Kovalenko National University of Pharmacy, Ukraine
  • T. Langer Wieden University, Austria

DOI:

https://doi.org/10.24959/ophcj.19.174807

Keywords:

1, 2, 4-triazolo[4, 3-a]pyridine, 4-oxadiazole, Pim-1 protein kinase, antitumor activity, pharmacophore model, virtual screening

Abstract

The Pim-1 enzyme from the serine/threonine protein kinase family is a likely target for the targeted therapy of tumors of hematopoietic and lymphoid tissues. Triazolopyridine is an universal scaffold upon which international scientific programs have been launched to develop potential anticancer agents.
Aim. To create a pharmacophore model to find new potential Pim-1 inhibitors; conduct a virtual screening of a simulated base of new 1,2,4-triazolo[4,3-a]pyridine derivatives; develop a method for the synthesis of 1,2,4-triazolo[4,3-a]pyridine-3-methanamines with the 1,2,4-isoxadiazole cycle.
Results and discussion. In this study, a ligand-based pharmacophore model for Pim-1 inhibitors was constructed and validated. A virtual screening of the library with 912 compounds resulted in a hit list of 175 compounds. For the synthesis, 15 compounds were selected with the highest pharmacophore-fit score. 15 compounds were synthesized as potential inhibitors of Pim-1 kinase.
Experimental part. The synthetic approach has been developed, and systematic series of new amides of (7-(1,2,4-oxadiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine and (8-(1,2,4-oxadiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine have been synthesized.
Conclusions. The compounds obtained are potential inhibitors of Pim-1 kinase. Further studies will focus on the determination of the antitumor activity of the compounds synthesized by in vitro and in vivo methods.

Downloads

Download data is not yet available.

References

  1. Cancer Facts and Figures. American Cancer Society. (2016). Available at: https://www.cancer.org/content/dam/cancer-org/research/cancerfacts-and-statistics/annual-cancer-facts-and-figures/2016/cancer-facts-and-figures-2016.pdf
  2. World Health Organization (WHO), Cancer key facts. (2017). Available at: https://www.who.int/cancer/media/news/cancer-key-facts/en/3. Nakhjiri, M., Safavi, M., Alipour, E., Emami, S., Atash, A. F., Jafari-Zavareh, M., … Shafiee, A. (2012). Asymmetrical 2,6-bis(benzylidene)cyclohexanones: Synthesis, cytotoxic activity and QSAR study. European Journal of Medicinal Chemistry, 50, 113–123. https://doi.org/10.1016/j.ejmech.2012.01.045
  3. Ananda Kumar, C. S., Nanjunda Swamy, S., Thimmegowda, N. R., Benaka Prasad, S. B., Yip, G. W., Rangappa, K. S. (2007). Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of MDA-MB-231 human breast cancer cell proliferation. Medicinal Chemistry Research, 16 (4), 179–187. https://doi.org/10.1007/s00044-007-9022-y
  4. Bachmann, M., Möröy, T. (2005). The serine/threonine kinase Pim-1. The International Journal of Biochemistry & Cell Biology, 37 (4), 726–730. https://doi.org/10.1016/j.biocel.2004.11.005
  5. Hsi, E. D., Jung, S.-H., Lai, R., Johnson, J. L., Cook, J. R., Jones, D., … Said, J. (2008). Ki67 and PIM1 expression predict outcome in mantle cell lymphoma treated with high dose therapy, stem cell transplantation and rituximab: a Cancer and Leukemia Group B 59909 correlative science study. Leukemia & Lymphoma, 49 (11), 2081–2090. https://doi.org/10.1080/10428190802419640
  6. Amson, R., Sigaux, F., Przedborski, S., Flandrin, G., Givol, D., Telerman, A. (1989). The human protooncogene product p33pim is expressed during fetal hematopoiesis and in diverse leukemias. Proceedings of the National Academy of Sciences, 86 (22), 8857–8861. https://doi.org/10.1073/pnas.86.22.8857
  7. Valdman, A., Fang, X., Pang, S.-T., Ekman, P., Egevad, L. (2004). Pim-1 expression in prostatic intraepithelial neoplasia and human prostate cancer. The Prostate, 60 (4), 367–371. https://doi.org/10.1002/pros.20064
  8. Beier, U., Weise, J., Laudien, M., Sauerwein, H., Görögh, T. (2007). Overexpression of Pim-1 in head and neck squamous cell carcinomas. International Journal of Oncology, 30, 1381–1387. https://doi.org/10.3892/ijo.30.6.1381
  9. Babel, I., Barderas, R., Díaz-Uriarte, R., Martínez-Torrecuadrada, J. L., Sánchez-Carbayo, M., Casal, J. I. (2009). Identification of Tumor-associated Autoantigens for the Diagnosis of Colorectal Cancer in Serum Using High Density Protein Microarrays. Molecular & Cellular Proteomics, 8 (10), 2382–2395. https://doi.org/10.1074/mcp.m800596-mcp200
  10. Arunesh, G. M., Shanthi, E., Krishna, M. H., Sooriya Kumar, J., Viswanadhan, V. N. (2013). Small molecule inhibitors of PIM1 kinase: July 2009 to February 2013 patent update. Expert Opinion on Therapeutic Patents, 24 (1), 5–17. https://doi.org/10.1517/13543776.2014.848196
  11. Blanco-Aparicio, C., Collazo, A. M. G., Oyarzabal, J., Leal, J. F., Albarán, M. I., Lima, F. R., … Bischoff, J. R. (2011). Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition. Cancer Letters, 300 (2), 145–153. https://doi.org/10.1016/j.canlet.2010.09.016
  12. Karpina, V. R., Kovalenko, S. S., Kovalenko, S. M., Zaremba, O. V., Silin, O. V., Langer, T. (2019). The synthesis and biological assessment of [[1,2,4]triazolo[4,3-a]pyridine-3-yl]acetamides with an 1,2,4-oxadiazol cycle in positions 6, 7 and 8. Journal of Organic and Pharmaceutical Chemistry, 17 (65), 28–35. https://doi.org/10.24959/ophcj.19.965
  13. Patent WO004984. (2013). Tricyclic compounds for use as kinase inhibitors. Centro Nacional de Investigaciones Oncologicas (CNIO).
  14. Patent WO022076. (2010). Triazolopyridine compounds as PIM kinase inhibitors. Array Biopharma, Inc.
  15. Patent WO022081. (2010). Triazolopyridine compounds as PIM kinase inhibitors. Array Biopharma, Inc.
  16. Duanmu, C., Shahrik, L. K., Ho, H. H., Hamel, E. (1989). Tubulin-dependent hydrolysis of Guanosine Triphosphate as a screening test to identify new antitubulin compounds with potential as antimitotic agents: application to carbamates of aromatic amines. Cancer Research, 49, 1344–1348.
  17. Shahzad, S. A., Yar, M., Bajda, M., Jadoon, B., Khan, Z. A., Naqvi, S. A. R., … Filipek, S. (2014). Synthesis and biological evaluation of novel oxadiazole derivatives: A new class of thymidine phosphorylase inhibitors as potential anti-tumor agents. Bioorganic & Medicinal Chemistry, 22 (3), 1008–1015. https://doi.org/10.1016/j.bmc.2013.12.043
  18. Kemnitzer, W., Kuemmerle, J., Zhang, H.-Z., Kasibhatla, S., Tseng, B., Drewe, J., Cai, S. X. (2009). Discovery of 3-aryl-5-aryl-1,2,4-oxadiazoles as a new series of apoptosis inducers. 2. Identification of more aqueous soluble analogs as potential anticancer agents. Bioorganic & Medicinal Chemistry Letters, 19 (15), 4410–4415. https://doi.org/10.1016/j.bmcl.2009.05.052
  19. El-Garhy, O. H. (2015). An overview of the azoles of interest. International Journal of Current Pharmaceutical Research, 7 (1), 1–6.
  20. Wermuth, C. G., Ganellin, C. R., Lindberg, P., Mitscher, L. A. (1998). Glossary of terms used in medicinal chemistry (IUPAC Recommendations). Pure and Applied Chemistry, 70, 1129−1143. https://doi.org/10.1515/iupac.70.0050
  21. Gao, Q., Yang, L., Zhu, Y. (2010). Pharmacophore Based Drug Design Approach as a Practical Process in Drug Discovery. Current Computer Aided-Drug Design, 6 (1), 37–49. https://doi.org/10.2174/157340910790980151
  22. Mysinger, M. M., Carchia, M., Irwin, J. J., & Shoichet, B. K. (2012). Directory of Useful Decoys, Enhanced (DUD-E): Better Ligands and Decoys for Better Benchmarking. Journal of Medicinal Chemistry, 55 (14), 6582–6594. https://doi.org/10.1021/jm300687e
  23. Sterling, T., Irwin, J. J. (2015). ZINC 15 – Ligand Discovery for Everyone. Journal of Chemical Information and Modeling, 55 (11), 2324–2337. https://doi.org/10.1021/acs.jcim.5b00559
  24. Wolber, G., Langer, T. (2005). Ligand Scout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. Journal of Chemical Information and Modeling, 45, 160–169.
  25. Wolber, G., Dornhofer, A. A., & Langer, T. (2006). Efficient overlay of small organic molecules using 3D pharmacophores. Journal of Computer-Aided Molecular Design, 20(12), 773–788. https://doi.org/10.1007/s10822-006-9078-7
  26. Wolber, G., Seidel, T., Bendix, F., Langer, T. (2008). Molecule pharmacophore super positioning and pattern matching in computational drug design. Drug Discovery Today, 13, 23–29.
  27. Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeabilityy in drug discovery and development settings. Adv. Drug Delivery Rev., 46, 3−26. https://doi.org/10.1016/s0169-409x(00)00129-0
  28. Daina, A., Michielin, O., & Zoete, V. (2019). SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research, 47(W1), W357–W364. https://doi.org/10.1093/nar/gkz382

Downloads

Published

2019-08-28

How to Cite

(1)
Karpina, V. R.; Kovalenko, S. M.; Zaremba, O. V.; Silin, O. V.; Ivanov, V. V.; Kovalenko, S. S.; Langer, T. The Search for Potential Inhibitors of Protein Kinase Pim-1 Among New Amides of 1,2,4-triazolo[4,3-a]pyridine-3-Metanamin With the 1,2,4-Oxadiazol Cycle in Position 7 and 8. J. Org. Pharm. Chem. 2019, 17, 5-14.

Issue

Vol. 17 No. 3(67) (2019)

Section

Original Researches

License

Copyright (c) 2019 National University of Pharmacy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:

1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.

3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).