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

Abstract

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.

Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer

“…We hypothesize that the basic 5-(5-(diethylamino)­pentan-2-yl)­amine tail moiety in CQ is responsible for σ1R binding. Recently, we identified the quinolyl pyrazinamide derivative QN523 as a promising lead compound, exhibiting significant cytotoxicity in pancreatic cancer cell lines . Accordingly, we thought to append the basic tail moiety of CQ to QN523 to explore this functional group for the identification of cytotoxic σR ligands exemplified by the hybrid structure 1 (Figure ).…”

“…Recently, we identified the quinolyl pyrazinamide derivative QN523 as a promising lead compound, exhibiting significant cytotoxicity in pancreatic cancer cell lines. 47 Accordingly, we thought to append the basic tail moiety of CQ to QN523 to explore this functional group for the identification of cytotoxic σR ligands exemplified by the hybrid structure 1 (Figure 2). Grafting the CQ tail moiety allows for salt formation and potentially improves the solubility of the whole molecule.…”