Active fragment assembly strategy enabling fast discovery of KRAS inhibitors against pancreatic cancer cells.

The escalating demand for efficient therapeutic development necessitates innovative strategies to accelerate drug discovery. This study employs an active fragment assembly (AFA) strategy to create a series of linear indoxadiazole compounds that serve as viable inhibitors for KRAS protein. Preliminary assessments indicate that compound 10b exhibits significant inhibitory activity in pancreatic cancer cells harboring KRASG12C and KRASG12D mutations (ASPC-1, PANC-1 and Miapac-2) and excellent selectivity between cancerous and non-cancerous cells. Mechanistic studies reveal that 10b effectively downregulates the levels of phosphorylated Raf1, AKT, and ERK in the ASPC-1 and Miapac-2 cancer cell lines. Additionally, molecular docking studies demonstrate a robust binding affinity of compound 10b with both KRASG12C and KRASG12D proteins. These findings provided unique pathways for investigating multi-target inhibitors aimed at mutated KRAS proteins, thereby advancing the development of innovative molecular therapies for cancers associated with KRAS mutations.