Publication Date:
2013-05-24
Description:
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 PDEdelta, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEdelta 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-PDEdelta interaction that selectively bind to the prenyl-binding pocket of PDEdelta 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zimmermann, Gunther -- Papke, Bjorn -- Ismail, Shehab -- Vartak, Nachiket -- Chandra, Anchal -- Hoffmann, Maike -- Hahn, Stephan A -- Triola, Gemma -- Wittinghofer, Alfred -- Bastiaens, Philippe I H -- Waldmann, Herbert -- England -- Nature. 2013 May 30;497(7451):638-42. doi: 10.1038/nature12205. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698361" target="_blank"〉PubMed〈/a〉
Keywords:
Adenocarcinoma/drug therapy/genetics/metabolism
;
Animals
;
Benzimidazoles/*chemistry/metabolism/*pharmacology/therapeutic use
;
Binding Sites
;
Carcinoma, Pancreatic Ductal/drug therapy/genetics/metabolism
;
Cell Line
;
Cell Line, Tumor
;
Cell Proliferation/drug effects
;
Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists &
;
inhibitors/chemistry/*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/genetics/*metabolism
;
Protein Binding/drug effects
;
Signal Transduction/*drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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