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

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. [Display omitted] •AS1712 is active against broad cancer cell lines, even in drug resistant cells.•AS1712 is a low toxic colchicine-binding site inhibitor.•RJ-LC-15-8 had a greater anti-proliferative potency with a similar mechanism.•AS1712 and RJ-LC-15-8 can induce apoptosis in p-gp mediated MDR cells.•AS1712 and RJ-LC-15-8 have great potential for cancer therapy.