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
(17d) was identified, exhibiting balanced and robust
activity against PDEδ (KD = 0.410
nM) and NAMPT (IC50 = 2.21 nM). Notably, 17d demonstrated superior antitumor efficacy both in vitro and in vivo 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.