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

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

doi:10.1038/nature12205

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

Nature. 2013 May 30;497(7451):638-42. doi: 10.1038/nature12205. Epub 2013 May 22.

Authors

Gunther Zimmermann¹, Björn Papke, Shehab Ismail, Nachiket Vartak, Anchal Chandra, Maike Hoffmann, Stephan A Hahn, Gemma Triola, Alfred Wittinghofer, Philippe I H Bastiaens, Herbert Waldmann

Affiliation

¹ Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.

PMID: 23698361
DOI: 10.1038/nature12205

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors
Cyclic Nucleotide Phosphodiesterases, Type 6 / chemistry
Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism*
Dogs
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*
Protein Binding / drug effects
Signal Transduction / drug effects*

Substances

Benzimidazoles
deltarasin
Mitogen-Activated Protein Kinases
Cyclic Nucleotide Phosphodiesterases, Type 6
Oncogene Protein p21(ras)

Associated data

PDB/4JV6
PDB/4JV8
PDB/4JVB
PDB/4JVF