Identification of a new inhibitor of KRAS‐PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer

Oncogenic KRAS is considered a promising target for anti‐cancer therapy. However, direct pharmacological strategies targeting KRAS‐driven cancers remained unavailable. The prenyl‐binding protein PDEδ, a transporter of KRAS, has been identified as a potential target for pharmacological inhibitor by selectively binding to its prenyl‐binding pocket, impairing oncogenic KRAS signaling pathway. Here, we discovered a novel PDEδ inhibitor (E)‐N′‐((3‐(tert‐butyl)‐2‐hydroxy‐6,7,8,9‐tetrahydrodibenzo[b,dfuran‐1‐yl)methylene)‐2,4‐dihydroxybenzohydrazide(NHTD) by using a high‐throughput docking‐based virtual screening approach. In vitro and in vivo studies demonstrated that NHTD suppressed proliferation, induced apoptosis and inhibited oncogenic K‐RAS signaling pathways by disrupting KRAS‐PDEδ interaction in nonsmall cell lung cancer (NSCLC) harboring KRAS mutations. NHTD redistributed the localization of KRAS to endomembranes by targeting the prenyl‐binding pocket of PDEδ and exhibited the suppression of abnormal KRAS function. Importantly, NHTD prevented tumor growth in xenograft and KRAS mutant mouse model, which presents an effective strategy targeting KRAS‐driven cancer. What's new? Mutations in KRAS frequently are observed in cancer, resulting in aberrant signaling activity. This activity is strongly dependent on KRAS localization to the plasma membrane, a process modulated by phosphodiesterase 6 delta (PDEδ). Here, a promising PDEδ inhibitor, NHTD, was identified via analysis of interactions between PDEδ and compound libraries using an induced fit docking‐based screening approach. In KRAS‐mutant cells, NHTD disrupted KRAS‐PDEδ interaction by selectively attaching to its prenyl‐binding pocket. NHTD further reduced aberrant KRAS signaling and induced apoptosis. NHTD prevented tumor growth in mice. The findings warrant further investigation of NHTD as a potential therapy against KRAS‐driven cancer.