title: Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling.
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.
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Zimmermann
authors.forename: Björn
authors.initials: B
authors.lastname: Papke
authors.forename: Shehab
authors.initials: S
authors.lastname: Ismail
authors.forename: Nachiket
authors.initials: N
authors.lastname: Vartak
authors.forename: Anchal
authors.initials: A
authors.lastname: Chandra
authors.forename: Maike
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Hahn
authors.forename: Gemma
authors.initials: G
authors.lastname: Triola
authors.forename: Alfred
authors.initials: A
authors.lastname: Wittinghofer
authors.forename: Philippe I H
authors.initials: PI
authors.lastname: Bastiaens
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D006860:Hydrogen Bonding; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; C581772:deltarasin; D020928:Mitogen-Activated Protein Kinases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D015689:Oncogene Protein p21(ras)