2. Academic Validation
  3. 4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin

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

  • Eur J Med Chem. 2019 Nov 1:181:111584. doi: 10.1016/j.ejmech.2019.111584.
Ming-Shiu Lin 1,  Tse-Ming Hong 2,  Ting-Hung Chou 3,  Shuenn-Chen Yang 4,  Wei-Chia Chung 4,  Chia-Wei Weng 5,  Mei-Ling Tsai 3,  Ting-Jen Rachel Cheng 6,  Jeremy J W Chen 5,  Te-Chang Lee 1,  Chi-Huey Wong 6,  Rong-Jie Chein 7,  Pan-Chyr Yang 8
Affiliations

Affiliations

  • 1 Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
  • 2 Institute of Clinical Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
  • 3 Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan.
  • 4 Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
  • 5 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 402, Taiwan.
  • 6 The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
  • 7 Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan. Electronic address: rjchein@chem.sinica.edu.tw.
  • 8 Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, 100, Taiwan. Electronic address: pcyang@ntu.edu.tw.
PMID: 31419740 DOI: 10.1016/j.ejmech.2019.111584
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.

Keywords

Acquired resistance; Microtubule-targeting agents; p-glycoprotein.

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