SIOC 中文
CJOG
Adv search

Chinese Journal of Organic Chemistry >

2020 , Vol. 40 >Issue 1: 84 - 94

DOI: https://doi.org/10.6023/cjoc201904073

Discovery of a Novel FGFR4 Selective Inhibitor via Structure-Activity Relationship Studies of FGF401

  • Sun Chang'an ,
  • Fang Lei ,
  • Gou Shaohua
Expand
  • Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189

Received date: 2019-04-29

  Revised date: 2019-08-31

  Online published: 2019-09-18

Supported by

Project supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. 1107047002) and the National Science and Technology Major Foundation of China (No. 2013ZX09402102-001-006).

Fold

Abstract

A set of analogues of FRF401 were designed and synthesized, and their FGFR4 inhibition and antitumor activity as well as the structure-activity relationship (SAR) studies were screened. It was found that N-(5-cyano-4-((2-methoxyethyl)-amino)pyridin-2-yl)-7-formyl-6-((N-methyltetrahydro-2H-pyran-4-carboxamido)methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1-carboxamide (8ac) not only showed superior FGFR4 inhibitory activity compared with FGF401 and excellent selectivity in enzymatic and cellular level, but also dramatically inhibited tumor growth and induced tumor regression in hepatocellular carcinoma xenograft model.

Key words： selective FGFR4 inhibitor; analogues of FRF401; structure-activity relationship; hepatocellular carcinoma

Cite this article

Sun Chang'an , Fang Lei , Gou Shaohua . Discovery of a Novel FGFR4 Selective Inhibitor via Structure-Activity Relationship Studies of FGF401[J]. Chinese Journal of Organic Chemistry, 2020 , 40(1) : 84 -94 . DOI: 10.6023/cjoc201904073

References

[1] Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R. L.; Torre L. A.; Jemal A. CA:Cancer J. Clin. 2018, 68, 394.
[2] Keating, G. M.; Santoro, A. Drugs 2009, 69, 223.
[3] US Food and Drug Administration Approved Drugs-FDA Approves Lenvatinib for Unresectable Hepatocellular Carcinoma, Published Online:Aug 16, 2018. https://www.fda.gov/drugs/resources-infor-mation-approved-drugs/fda-approves-lenvatinib-unresectable-hepa-tocellular-carcinoma(accessed Jan 19, 2020).
[4] Ho, H. K.; Pok, S.; Streit, S.; Ruhe, J. E.; Hart, S.; Lim, K. S.; Loo, H. L.; Aung, M. O.; Lim, S. G.; Ullrich, A. J. Hepatol. 2009, 50, 118.
[5] Sawey, E. T.; Chanrion, M.; Cai, C. L.; Wu, G. M.; Zhang, J. P.; Zender, L.; Zhao, A.; Busuttil, R. W.; Yee, H. M.; Stein, L.; French, D. M.; Finn, R. S.; Lowe, S. W.; Powers, S. Cancer Cell 2011, 19, 347.
[6] Hyeon, J.; Ahn, S.; Lee, J. J.; Song, D. H.; Park, C. K. Dig. Dis. Sci. 2013, 58, 1916.
[7] Pinyol, R.; Nault, J. C.; Quetglas, I. M.; Zucman-Rossi, J.; Llovet, J. M. Semin. Liver Dis. 2014, 34, 363.
[8] Tucker, J. A.; Klein, T.; Breed, J.; Overman, R.; Phillips, C.; Norman, R. A. Structure 2014, 22, 1764.
[9] Llovet, J. M.; Villanueva, A.; Lachenmayer, A.; Finn, R. S. Nat. Rev. Clin. Oncol. 2015, 12, 408.
[10] Repana, D.; Ross, P. Diseases 2015, 3, 294.
[11] Lu, X. Y.; Chen, H.; Patterson, A. V.; Smaill, J. B.; Ding, K. J. Med. Chem. 2019, 62, 2905.
[12] Hagel, M.; Miduturu, C.; Sheets, M.; Rubin, N.; Weng, W.; Stransky, N.; Bifulco, N.; Kim, J. L.; Hodous, B.; Brooijmans, N.; Shutes, A.; Winter, C.; Lengauer, C.; Kohl, N. E.; Guzi, T. Cancer Discovery 2015, 5, 424.
[13] Joshi, J. J.; Coffey, H.; Corcoran, E.; Tsai, J.; Huang, C. L.; Ichikawa, K.; Prajapati, S.; Hao, M. H.; Bailey, S.; Wu, J. Cancer Res. 2017, 77, 6999.
[14] Mo, C.; Zhang, Z.; Guise, C. P.; Li, X.; Luo, J.; Tu, Z.; Xu, Y.; Patterson, A. V.; Smaill, J. B.; Ren, X. ACS Med. Chem. Lett. 2017, 8, 543.
[15] Wang, Y.; Chen, Z.; Dai, M.; Sun, P.; Wang, C.; Gao, Y.; Zhao, H.; Zeng, W.; Shen, L.; Mao, W. Bioorg Med. Chem. Lett. 2017, 27, 2420.
[16] Knoepfel, T.; Furet, P.; Mah, R.; Buschmann, N.; Leblanc, C.; Ripoche, S.; Graus-Porta, D.; Wartmann, M.; Galuba, I.; Fairhurst, R. A. ACS Med. Chem. Lett. 2018, 9, 215.
[17] Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.; Yang, C. H.; Wells, K. M.; Yau, J.; Palucki, M.; Tan, L. S.; Dormer, P. G.; Volante, R. P.; Hughes, D. L.; Reider, P. J. J. Org. Chem. 2004, 69, 1959.
[18] Novartis, A. G.; Buschmann, N.; Fairhurst, R. A.; Furet, P.; Knöpfel, T.; Leblanc, C.; Liao, L.; Wang, C.; Zhao, X. L. US 2015/119385, 2015.
Options
Outlines

/

〈 〉