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Chinese Journal of Organic Chemistry >

2020 , Vol. 40 >Issue 7: 1983 - 1990

DOI: https://doi.org/10.6023/cjoc201912033

Design, Synthesis and Antitumor Evaluation of Novel Small Molecule Extracellular Regulated Protein Kinase (ERK) Inhibitors

  • Zhu Zhongzhen ,
  • Qiao Yu ,
  • Zhang Zihao ,
  • Gu Mingzhen ,
  • Wang Jin ,
  • Gao Zhiyu ,
  • Guo Wenhao ,
  • Liu Mingming ,
  • Li Rong
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  • School of Pharmacy, Anhui Medical University, Hefei 230032

Received date: 2019-12-23

  Revised date: 2020-04-26

  Online published: 2020-04-30

Supported by

Project supported by the National Natural Science Foundation of China (No. 81972040).

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Abstract

Extracellular regulated protein kinase (ERK) is a key kinase in the development of cancer. 12 urea compounds containing morpholin rings were designed and synthesized in search of novel ERK inhibitors by using merging strategy. The structures of all compounds were confirmed by 1H NMR, 13C NMR and HRMS. ERK kinase activity and cell proliferation test results indicate that most of the target compounds have moderately inhibitory effects on human colorectal cancer cells SW480 and HCT-116, especially the IC50 of 1-(4-fluorobenzyl)-3-(5-(4-morpholinophenyl)pyridin-2-yl)urea (18f) reaches 0.36 and 0.55 μmol/L, respectively, and has low toxicity to normal cells L02 (>10 μmol/L). At the same time, 18f can inhibit ERK kinase activity (IC50=0.051 μmol/L) and phosphorylation level, but does not affect total ERK expression and upstream upstream activation of mitogen-activated extracellular signal-regulated kinase (MEK) activation. These research provides important reference for the further study of novel benzylpyridylurea ERK inhibitors.

Key words： mitogen-activated protein kinases(MAPKs); extracellular regulated protein kinase (ERK); diarylurea; synthesis; antitumor activity

Cite this article

Zhu Zhongzhen , Qiao Yu , Zhang Zihao , Gu Mingzhen , Wang Jin , Gao Zhiyu , Guo Wenhao , Liu Mingming , Li Rong . Design, Synthesis and Antitumor Evaluation of Novel Small Molecule Extracellular Regulated Protein Kinase (ERK) Inhibitors[J]. Chinese Journal of Organic Chemistry, 2020 , 40(7) : 1983 -1990 . DOI: 10.6023/cjoc201912033

References

[1] Roskoski, R. Jr. Pharmacol. Res. 2012, 66, 105.
[2] Roberts, P. J.; Der, C. J. Oncogene 2007, 26, 3291.
[3] Uehling, D. E.; Harris, P. A. Bioorg. Med. Chem. Lett. 2015, 25, 4047.
[4] Morris, E. J.; Jha, S.; Restaino, C. R.; Dayananth, P.; Zhu, H.; Cooper, A.; Carr, D.; Deng, Y.; Jin, W.; Black, S.; Long, B.; Liu, J.; Dinunzio, E.; Windsor, W.; Zhang, R.; Zhao, S.; Angagaw, M. H.; Pinheiro, E. M.; Desai, J.; Xiao, L.; Shipps, G.; Hruza, A.; Wang, J.; Kelly, J.; Paliwal, S.; Gao, X.; Babu, B. S.; Zhu, L.; Daublain, P.; Zhang, L.; Lutterbach, B. A.; Pelletier, M. R.; Philippar, U.; Siliphaivanh, P.; Witter, D.; Kirschmeier, P.; Bishop, W. R.; Hicklin, D.; Gilliland, D. G.; Jayaraman, L.; Zawel, L.; Fawell, S.; Samatar, A. A. Cancer Discovery 2013, 3, 742.
[5] Blake, J. F.; Burkard, M.; Chan, J.; Chen, H.; Chou, K. J.; Diaz, D.; Dudley, D. A.; Gaudino, J. J.; Gould, S. E.; Grina, J.; Hunsaker, T.; Liu, L.; Martinson, M.; Moreno, D.; Mueller, L.; Orr, C.; Pacheco, P.; Qin, A.; Rasor, K.; Ren, L.; Robarge, K.; Shahidi-Latham, S.; Stults, J.; Sullivan, F.; Wang, W.; Yin, J.; Zhou, A.; Belvin, M.; Merchant, M.; Moffat, J.; Schwarz, J. B. J. Med. Chem. 2016, 59, 5650.
[6] Bhagwat, S. V.; McMillen, W. T.; Cai, S.; Zhao, B.; Whitesell, M.; Shen, W.; Kindler, L.; Flack, R. S.; Wu, W.; Anderson, B.; Zhai, Y.; Yuan, X. J.; Pogue, M.; Van Horn, R. D.; Rao, X.; McCann, D.; Dropsey, A. J.; Manro, J.; Walgren, J.; Yuen, E.; Rodriguez, M. J.; Plowman, G. D.; Tiu, R. V.; Joseph, S.; Peng, S. B. Mol. Cancer Ther. 2020, 19, 325.
[7] Lim, J.; Kelley, E. H.; Methot, J. L.; Zhou, H.; Petrocchi, A.; Chen, H.; Hill, S. E.; Hinton, M. C.; Hruza, A.; Jung, J. O.; Maclean, J. K.; Mansueto, M.; Naumov, G. N.; Philippar, U.; Raut, S.; Spacciapoli, P.; Sun, D.; Siliphaivanh, P. J. Med. Chem. 2016, 59, 6501.
[8] Heightman, T. D.; Berdini, V.; Braithwaite, H.; Buck, I. M.; Cassidy, M.; Castro, J.; Courtin, A.; Day, J. E. H.; East, C.; Fazal, L.; Graham, B.; Griffiths-Jones, C. M.; Lyons, J. F.; Martins, V.; Muench, S.; Munck, J. M.; Norton, D.; O'Reilly, M.; Palmer, N.; Pathuri, P.; Reader, M.; Rees, D. C.; Rich, S. J.; Richardson, C.; Saini, H.; Thompson, N. T.; Wallis, N. G.; Walton, H.; Wilsher, N. E.; Woolford, A. J.; Cooke, M.; Cousin, D.; Onions, S.; Shannon, J.; Watts, J.; Murray, C. W. J. Med. Chem. 2018, 61, 4978.
[9] Yamamoto, T.; Morita, T.; Takagi, J.; Yamakawa, T. Org. Lett. 2011, 13, 5766.
[10] Sun, C. L.; Liang, C. X.; Huang, P.; Harris, G. D.; Guan, H. P. US 20040220189, 2004.
[11] Monte, F. L.; Kramer, T.; Bolander, A.; Plotkin, B.; Eldar- Finkelman, H.; Fuertes, A.; Dominguez, J.; Schmidt, B. Bioorg. Med. Chem. Lett. 2011, 21, 5610.
[12] Song, S.; Sun, X.; Li, X.; Yuan, Y.; Jiao, N. Org. Lett. 2015, 17, 2886.
[13] Patel, G.; Karver, C. E.; Behera, R.; Guyett, P. J.; Sullenberger, C.; Edwards, P.; Roncal, N. E.; Mensa-Wilmot, K.; Pollastri, M. P. J. Med. Chem. 2013, 56, 3820.
[14] Dow, R. L.; Ammirati, M.; Bagley, S. W.; Bhattacharya, S. K.; Buckbinder, L.; Cortes, C.; El-Kattan, A. F.; Ford, K.; Freeman, G. B.; Guimaraes, C. R. W.; Liu, S.; Niosi, M.; Skoura, A.; Tess, D. J. Med. Chem. 2018, 61, 3114.
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