title: Structure-based development of PDEδ inhibitors.
abstract: The prenyl binding protein PDEδ enhances the diffusion of farnesylated Ras proteins in the cytosol, ultimately affecting their correct localization and signaling. This has turned PDEδ into a promising target to prevent oncogenic KRas signaling. In this review we summarize and describe the structure-guided-development of the three different PDEδ inhibitor chemotypes that have been documented so far. We also compare both their potency for binding to the PDEδ pocket and their in vivo efficiency in suppressing oncogenic KRas signaling, as a result of the inhibition of the PDEδ/KRas interaction.
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martín-Gago
authors.affiliation: Structural Biology Group, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund.
authors.forename: Eyad Kalawy
authors.initials: EK
authors.lastname: Fansa
authors.affiliation: Structural Biology Group, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund.
authors.forename: Alfred
authors.initials: A
authors.lastname: Wittinghofer
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors*; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011724:Pyridazines; C062482:pyridazine; C031000:benzimidazole; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6
keywords: KRas; PDEδ; small molecules; structure-based design; structure-property-relationships