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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Atorvastatin
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacology
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Binding Sites
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Cell Line, Tumor
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Computer Simulation
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Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors*
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Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism
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Drug Design
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Esters
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Ethers / chemical synthesis
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Ethers / chemistry
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Ethers / pharmacology
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Heptanoic Acids / chemical synthesis
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Heptanoic Acids / chemistry
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Heptanoic Acids / pharmacology
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Humans
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Kinetics
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Models, Molecular
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Protein Prenylation
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Thermodynamics
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ras Proteins / metabolism
Substances
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Benzimidazoles
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Esters
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Ethers
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Heptanoic Acids
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Pyrroles
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deltarasin
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Atorvastatin
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Cyclic Nucleotide Phosphodiesterases, Type 6
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ras Proteins