Design of balanced dual-target inhibitors of EGFR and microtubule.

Motivated by the clinical success of combining tyrosine kinase inhibitors with microtubule-targeted drugs in antitumor treatment, this paper presents a novel combi-targeting design for dual-target inhibitors, featuring arylformylurea-coupled quinazoline backbones. A series of target compounds (10a-10r) were designed, synthesized, and characterized. Biological assessments demonstrated that 10c notably potentiated ten tumor cell lines in vitro, with IC50 values ranging from 1.04 µM to 7.66 µM. Importantly, 10c (IC50 = 10.66 nM) exhibited superior inhibitory activity against EGFR kinases compared to the reference drug Gefitinib (25.42 nM) and reduced phosphorylated levels of EGFR, AKT, and ERK. Moreover, 10c significantly impeded tubulin polymerization, disrupted the intracellular microtubule network in A549 cells, induced apoptosis, led to S-phase cell cycle arrest, and hindered cell migration. In anticancer evaluation tests using A549 cancer-bearing nude mice models, 10c showed a therapeutic effect similar to Gefitinib, but required only half the dosage (15 mg/kg). These findings indicate that compound 10c is a promising dual-target candidate for anticancer therapy.

Design, synthesis and antitumor activity of aromatic urea-quinazolines.

Background: Gefitinib and sorafenib have been proved effective for the treatment of cancers in clinical practice for years. Materials & methods: We intended to integrate the structural features of gefitinib and sorafenib and construct structurally unique 7-aromatic ureido-4-anilinoquinazolines. Results: Most of the targets exhibited promising antitumor activities. 8u showed excellent antitumor activities against the three tested cell lines (IC50, 0.81-2.49 µM). The enzymatic, apoptosis assay of 8u were also performed to study their preliminary action of mechanism. Conclusion: 8u deserve further research as antitumor agents.