Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

KRAS-PDE delta interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDE delta inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDE delta inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 361 (K-D = 127 +/- 16 nmol/L) effectively bound to PDE delta and interfered with KRAS-PDE delta interaction. It influenced the distribution of KRAS in Mia PaCa2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 361 exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRAS-PDE delta interaction. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.