Deltarasin is the potent and selective small molecular inhibitor of KRAS-PDEδ interaction, selectively binds to the prenyl-binding pocket of PDEδ with 38 nM affinity. It can inhibit oncogenic RAS signaling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Deltarasin provides a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes, and may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.