Copper-KRAS-COX2 Axis: A Therapeutic Vulnerability in Pancreatic Cancer

KRAS mutations are a hallmark of pancreatic ductal adenocarcinoma (PDAC), occurring in over 90% of tumors. Tumors with these mutations are highly dependent on copper, making the targeting of copper homeostasis an attractive strategy for treating PDAC due to the higher copper requirement of cancer cells compared to normal cells. Herein, we present the discovery, lead optimization, and structure–activity relationship study of a series of novel quinolyl pyrazinamides for the treatment PDAC. These compounds induce cell death through copper-mediated apoptosis and necroptosis. Our optimized compounds, 39 and 52, are potent, water-soluble and metabolically stable. Compound 52 exhibits 55% oral bioavailability and demonstrates significant in vivo efficacy without obvious toxicity in syngeneic models of PDAC. Additionally, compound 52 showed significant synergy with celecoxib, a selective COX2 inhibitor, both in vitro and in vivo. Our data suggest that compound 52 is a promising candidate for further development in KRAS-mutated cancers.