Induction of Genes Implicated in Stress Response and Autophagy bya Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer

摘要

Using a cytotoxicity-based phenotypic screen of a highly diverse library of 20,000small-molecule compounds, we identified a quinolin-8-yl-nicotinamide, QN519, as a promisinglead. QN519 represents a novel scaffold with drug-like properties, showing potentin vitrocytotoxicity in a panel of 12 cancer cell lines. Subsequently, lead optimization campaign generatedcompounds with IC50values < 1 mu M. An optimized compound, QN523, shows significantin vivoefficacy in a pancreatic cancer xenograft model. QN523 treatment significantly increased theexpression of HSPA5, DDIT3, TRIB3, and ATF3 genes, suggesting activation of the stressresponse 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 tothe lack of effective treatments for pancreatic cancer, discovery of novel agents such as the QNseries of compounds with unique mechanism of action has the potential to fulfill a clear unmetmedical need