A novel Quinazoline derivative exerts anti-tumor effects in non-small cell lung cancer through Wnt/β-catenin pathway inhibition

4-anilinoquinazoline scaffold, a key structure in the development of EGFR-TKI Anticancer drugs such as Gefitinib and Erlotinib, continues to drive advancements in non-small cell lung Cancer (NSCLC) therapy. In this study, we synthesized a series of novel derivatives (B3-B11). Structure-activity relationship (SAR) analysis revealed that electron-donating groups para-substituted at the 4-anilino position significantly enhanced antiproliferative activity. Notably, B10 incorporating an acrylamide group at the 4-anilino position demonstrated the most potent activity against NSCLC, with an IC₅₀ of 1.28 μM in A549 cells, nearly six times more effective than Gefitinib (7.81 μM). Acute toxicity studies confirmed that B10 is safe at doses below 50 mg/kg. In vivo studies using an A549 xenograft model showed a 46 % tumor growth inhibition (TGI) with B10 (25 mg/kg), surpassing the 21 % inhibition of Gefitinib at the same dose. Mechanistic studies revealed that B10 inhibited the Akt/GSK-3β/β-catenin signaling pathway, downregulating Wnt target genes (c-Myc, c-Jun), and reduced COX2 expression and IL-8 levels, showcasing its dual anti-inflammatory and antitumor effects. These results position B10 as a promising NSCLC therapeutic candidate, combining potent efficacy with a favorable safety profile, and enhance our understanding of the SAR and mechanism of action of 4-anilinoquinazoline derivatives.

4-anilinoquinazoline derivatives; Antitumor agents; NSCLC; SAR; Wnt/β-catenin pathway.