4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin

Ming Shiu Lin, Tse Ming Hong, Ting Hung Chou, Shuenn Chen Yang, Wei Chia Chung, Chia Wei Weng, Mei Ling Tsai, Ting Jen Rachel Cheng, Jeremy J.W. Chen, Te Chang Lee, Chi Huey Wong, Rong Jie Chein, Pan Chyr Yang

研究成果: Article

4 引文 斯高帕斯(Scopus)

摘要

Developing new therapeutic strategies to overcome drug resistance of cancer cells is an ongoing endeavor. From among 2 million chemicals, we identified ethyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (AS1712) as a low-toxicity inhibitor of lung cancer cell proliferation and xenograft tumor growth. We show that AS1712 is active against broad cancer cell lines and is able to bind in the colchicine-binding pocket of β-tubulin, thereby inhibiting microtubule assembly and, consequently, inducing mitotic arrest and apoptosis. Our cell-based structure-activity relationship study identified a new lead compound, RJ-LC-15-8, which had a greater anti-proliferative potency for H1975 cells than did AS1712, while maintaining a similar mechanism of action. Notably, AS1712 and RJ-LC-15-8 overcame P-glycoprotein efflux pump and β-tubulin alterations that lead to acquired resistance against microtubule-targeting drugs of cancer cells. AS1712 and RJ-LC-15–8 may be lead compounds that overcome acquired resistance to microtubule-targeting agents of cancer cells.

原文English
文章編號111584
期刊European Journal of Medicinal Chemistry
181
DOIs
出版狀態Published - 2019 十一月 1

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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    Lin, M. S., Hong, T. M., Chou, T. H., Yang, S. C., Chung, W. C., Weng, C. W., Tsai, M. L., Cheng, T. J. R., Chen, J. J. W., Lee, T. C., Wong, C. H., Chein, R. J., & Yang, P. C. (2019). 4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin. European Journal of Medicinal Chemistry, 181, [111584]. https://doi.org/10.1016/j.ejmech.2019.111584