title: Structure guided design and kinetic analysis of highly potent benzimidazole inhibitors targeting the PDEδ prenyl binding site.
abstract: K-Ras is one of the most frequently mutated signal transducing human oncogenes. Ras signaling activity requires correct cellular localization of the GTPase. The spatial organization of K-Ras is controlled by the prenyl binding protein PDEδ, which enhances Ras diffusion in the cytosol. Inhibition of the Ras-PDEδ interaction by small molecules impairs Ras localization and signaling. Here we describe in detail the identification and structure guided development of Ras-PDEδ inhibitors targeting the farnesyl binding pocket of PDEδ with nanomolar affinity. We report kinetic data that characterize the binding of the most potent small molecule ligands to PDEδ and prove their binding to endogenous PDEδ in cell lysates. The PDEδ inhibitors provide promising starting points for the establishment of new drug discovery programs aimed at cancers harboring oncogenic K-Ras.
authors.affiliation: Max Planck Institute of Molecular Physiology , Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Zimmermann
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.forename: Philipp
authors.initials: P
authors.lastname: Küchler
authors.forename: Sandip
authors.initials: S
authors.lastname: Murarka
authors.forename: Shehab
authors.initials: S
authors.lastname: Ismail
authors.forename: Gemma
authors.initials: G
authors.lastname: Triola
authors.forename: Peter
authors.initials: P
authors.lastname: Nussbaumer
authors.forename: Alfred
authors.initials: A
authors.lastname: Wittinghofer
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000069059:Atorvastatin; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004952:Esters; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006538:Heptanoic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D017368:Protein Prenylation; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D018631:ras Proteins / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D004952:Esters; D004987:Ethers; D006538:Heptanoic Acids; D011758:Pyrroles; C581772:deltarasin; D000069059:Atorvastatin; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D018631:ras Proteins