Using a cytotoxicity-based phenotypic screen of a highly diverse library of 20,000 small-molecule compounds, we identified a quinolin-8-yl-nicotinamide, QN519, as a promising lead. QN519 represents a novel scaffold with drug-like properties, showing potent in vitro cytotoxicity in a panel of 12 cancer cell lines. Subsequently, lead optimization campaign generated compounds with IC50 values < 1 μM. An optimized compound, QN523, shows significant in vivo efficacy in a pancreatic cancer xenograft model. QN523 treatment significantly increased the expression of HSPA5, DDIT3, TRIB3, and ATF3 genes, suggesting activation of the stress response pathway. We also observed a significant increase in the expression of WIPI1, HERPUD1, GABARAPL1, and MAP1LC3B, implicating autophagy as a major mechanism of action. Due to the lack of effective treatments for pancreatic cancer, discovery of novel agents such as the QN series of compounds with unique mechanism of action has the potential to fulfill a clear unmet medical need.