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 journalArticle

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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

Fingerprint

4-Quinolones
Quinolones
Colchicine
Tubulin
Microtubules
Cells
Lead compounds
Derivatives
Neoplasms
Cell proliferation
P-Glycoprotein
Heterografts
Toxicity
Tumors
Drug Delivery Systems
Structure-Activity Relationship
Drug Resistance
Pumps
Apoptosis
Lung Neoplasms

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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 ; Yang, Pan Chyr. / 4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 181.
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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.",
author = "Lin, {Ming Shiu} and Hong, {Tse Ming} and Chou, {Ting Hung} and Yang, {Shuenn Chen} and Chung, {Wei Chia} and Weng, {Chia Wei} and Tsai, {Mei Ling} and Cheng, {Ting Jen Rachel} and Chen, {Jeremy J.W.} and Lee, {Te Chang} and Wong, {Chi Huey} and Chein, {Rong Jie} and Yang, {Pan Chyr}",
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Lin, MS, Hong, TM, Chou, TH, Yang, SC, Chung, WC, Weng, CW, Tsai, ML, Cheng, TJR, Chen, JJW, Lee, TC, Wong, CH, Chein, RJ & Yang, PC 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, vol. 181, 111584. https://doi.org/10.1016/j.ejmech.2019.111584

4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin. / 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; Yang, Pan Chyr.

In: European Journal of Medicinal Chemistry, Vol. 181, 111584, 01.11.2019.

Research output: Contribution to journalArticle

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AU - Lin, Ming Shiu

AU - Hong, Tse Ming

AU - Chou, Ting Hung

AU - Yang, Shuenn Chen

AU - Chung, Wei Chia

AU - Weng, Chia Wei

AU - Tsai, Mei Ling

AU - Cheng, Ting Jen Rachel

AU - Chen, Jeremy J.W.

AU - Lee, Te Chang

AU - Wong, Chi Huey

AU - Chein, Rong Jie

AU - Yang, Pan Chyr

PY - 2019/11/1

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N2 - 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.

AB - 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.

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