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

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number111584
JournalEuropean Journal of Medicinal Chemistry
Volume181
DOIs
Publication statusPublished - 2019 Nov 1

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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