4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin
Journal
European journal of medicinal chemistry
Journal Volume
181
Date Issued
2019-11-01
Author(s)
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
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.
Subjects
Acquired resistance; Microtubule-targeting agents; p-glycoprotein
SDGs
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Type
journal article