Journal Article

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

Hoffmann, Maike, Triola, Gemma, Ismail, Shehab, Zimmermann, Gunther, Bastiaens, Philippe I H, Waldmann, Herbert, Hahn, Stephan A, Vartak, Nachiket, Papke, Björn, Chandra, Anchal, Wittinghofer, Alfred

2013

Overview

The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling 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. Here we report that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEδ interaction that selectively bind to the prenyl-binding pocket of PDEδ with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.

• Publisher: Nature Publishing Group
• Subject: Adenocarcinoma - drug therapy / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Animals / Benzimidazoles - chemistry / Benzimidazoles - metabolism / Benzimidazoles - pharmacology / Benzimidazoles - therapeutic use / Binding Sites / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - metabolism / Cell Line / Cell Line, Tumor / Cell Proliferation - drug effects / Cell research / Crystals / Cyclic Nucleotide Phosphodiesterases, Type 6 - antagonists & inhibitors / Cyclic Nucleotide Phosphodiesterases, Type 6 - chemistry / Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism / Dogs / Fluorescence microscopy / Humans / Hydrogen Bonding / MAP Kinase Signaling System - drug effects / Mice / Mice, Nude / Mitogen-Activated Protein Kinases - metabolism / Models, Molecular / Molecular Conformation / Neoplasm Transplantation / Oncogene Protein p21(ras) - antagonists & inhibitors / Oncogene Protein p21(ras) - genetics / Oncogene Protein p21(ras) - metabolism / Peptides / Properties / Protein Binding - drug effects / Ras genes / Signal Transduction - drug effects / Structure