Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS is a key target in cancer drug discovery, but direct inhibition has proven challenging.
• The prenyl-binding protein PDEδ regulates KRAS localization and signaling by controlling its diffusion.
• Altering KRAS localization is a potential strategy to suppress oncogenic RAS signaling.

Purpose of the Study:

• To investigate small molecules that interfere with the KRAS-PDEδ interaction.
• To explore a novel approach for suppressing oncogenic RAS signaling by targeting KRAS localization.
• To develop inhibitors of the KRAS-PDEδ interaction for potential anticancer therapies.

Main Methods:

• Biochemical screening to identify inhibitors of the KRAS-PDEδ interaction.
• Structure-based drug design for hit optimization.
• Assays to evaluate inhibition of oncogenic RAS signaling and cancer cell proliferation in vitro and in vivo.

Main Results:

• Identification of small molecules that selectively bind to PDEδ with nanomolar affinity.
• Demonstration that these inhibitors disrupt the KRAS-PDEδ interaction.
• Suppression of oncogenic RAS signaling and proliferation of KRAS-dependent pancreatic cancer cells.

Conclusions:

• Targeting the KRAS-PDEδ interaction with small molecules is a viable strategy for suppressing oncogenic RAS signaling.
• Inhibitors of the KRAS-PDEδ interaction show potential for treating KRAS-dependent cancers, particularly pancreatic ductal adenocarcinoma.
• This approach offers a novel avenue for anticancer drug discovery efforts targeting KRAS.