Discovery of quinazoline-based derivatives as novel autophagy inhibitors in pancreatic cancer.

Pancreatic cancer remains a highly lethal malignancy with limited treatment options. Given the versatile bioactivity of quinazoline derivatives, which are regarded as a promising scaffold for anticancer drug discovery, we designed and synthesized a series of novel quinazoline analogues. Their cytotoxicity was evaluated in three pancreatic cancer cell lines (HPAC, AsPC-1, and MIA PaCa-2), leading to the identification of compound 5a, which exhibited potent effects across all tested cell lines. Further investigation of anticancer activity indicated that 5a significantly inhibited DNA synthesis, clonogenesis, and migration in MIA PaCa-2 cells. Mechanism study revealed that 5a disrupted autophagy, as evidenced by downregulation of Beclin-1 expression and accumulation of LC3B-II and p62, through a mechanism independent of the canonical AMPK-mTOR-ULK1 signaling pathway. This study provides a promising active scaffold for the development of anti-pancreatic cancer agents.