AQ-4, a deuterium-containing molecule, acts as a microtubule-targeting agent for cancer treatment

The important physiological function of microtubules makes them an indispensable and clinically effective target of anti-tumor agents. Herein, we sought to design, synthesize, and evaluate a novel 4-anilinoquinazoline derivative and identify its anti-tumor activity in vitro and in vivo. The novel compound, N -(4-methoxyphenyl)- N -methyl-2-(methyl- d 3 )quinazolin-4-amine ( AQ-4 ), was identified as a representative scaffold and potent microtubule-targeting agent. As a promising antimitotic agent , AQ-4 displayed remarkable anti-tumor activity with an average IC 50 value of 19 nM across a panel of 14 human cancer cell lines. AQ-4 also exhibited nearly identical potent activities against drug-resistant cells, with no evidence of toxicity towards normal cells. A further target verification study revealed that AQ-4 targets the tubulin-microtubule system by significantly inhibiting tubulin polymerization and disrupting the intracellular microtubule spindle dynamics. According to the results of mechanism study, AQ-4 induced cell cycle arrest in the G 2 /M phase, promoting evident apoptosis and a collapses of mitochondrial membrane potential . The superior anti-tumor effect of AQ-4 in vivo suggests that it should be further investigated to validate its use for cancer therapy.