https://scholars.lib.ntu.edu.tw/handle/123456789/626950
標題: | 4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin | 作者: | Lin, Ming-Shiu Hong, Tse-Ming Chou, Ting-Hung Yang, Shuenn-Chen Chung, Wei-Chia Weng, Chia-Wei Tsai, Mei-Ling Cheng, Ting-Jen Rachel Chen, Jeremy J W Lee, Te-Chang Wong, Chi-Huey Chein, Rong-Jie PAN-CHYR YANG |
關鍵字: | Acquired resistance; Microtubule-targeting agents; p-glycoprotein | 公開日期: | 1-十一月-2019 | 出版社: | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | 卷: | 181 | 來源出版物: | European journal of medicinal chemistry | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/626950 | ISSN: | 0223-5234 | DOI: | 10.1016/j.ejmech.2019.111584 |
顯示於: | 醫學系 |
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