Discovery of Potent PDEδ/NAMPT Dual Inhibitors: Preclinical Evaluation in KRAS Mutant Pancreatic Cancer Cells

Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are a common type of oncogenic mutation, widely observed in various cancers. The trafficking chaperone PDE6D (or PDEδ) has been proposed as an alternative target for KRAS, which has led to the preclinical evaluation of PDEδ inhibitors for targeting KRAS mutant cancers. In this study, inspired by the synergistic effect between PDEδ and nicotinamide phosphoribosyl transferase (NAMPT), we report the discovery of the first PDEδ/NAMPT dual inhibitors, which may serve as an interesting starting point for targeting KRAS mutant pancreatic cancer cell lines (MiaPaca-2). Among these, a highly potent dual inhibitor (<b>17d</b>) was identified, exhibiting balanced and robust activity against PDEδ (<i>K</i>_D = 0.410 nM) and NAMPT (IC₅₀ = 2.21 nM). Notably, <b>17d</b> demonstrated superior antitumor efficacy both <i>in vitro</i> and <i>in vivo</i> compared to either PDEδ or NAMPT inhibitors alone or in combination, highlighting the potential of PDEδ/NAMPT dual inhibitors in treating KRAS mutant pancreatic cancer cell lines.