{"doi":"10.1021/jm500632s","title":"Structure Guided Design and Kinetic Analysis of Highly Potent Benzimidazole Inhibitors Targeting the PDEδ Prenyl Binding Site","abstract":null,"journal":"Journal of Medicinal Chemistry","year":2014,"id":636283,"datarank":0.6238324625039509,"base_score":4.1588830833596715,"endowment":4.1588830833596715,"self_citation_contribution":0.6238324625039509,"citation_network_contribution":0.0,"self_endowment_contribution":0.6238324625039509,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":63,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1651298,"name":"Carsten Schultz-Fademrecht","orcid":null,"position":1,"is_corresponding":false},{"id":1651299,"name":"Philipp Küchler","orcid":null,"position":2,"is_corresponding":false},{"id":1651300,"name":"Sandip Murarka","orcid":null,"position":3,"is_corresponding":false},{"id":629732,"name":"Shehab Ismail","orcid":"0000-0002-4150-1077","position":4,"is_corresponding":false},{"id":1651303,"name":"Gemma Triola","orcid":null,"position":5,"is_corresponding":false},{"id":1651306,"name":"Peter Nussbaumer","orcid":null,"position":6,"is_corresponding":false},{"id":1651307,"name":"Alfred Wittinghofer","orcid":null,"position":7,"is_corresponding":false},{"id":1548700,"name":"Herbert Waldmann","orcid":"0000-0002-9606-7247","position":8,"is_corresponding":false},{"id":1651297,"name":"Gunther Zimmermann","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"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.","is_dataset_classified":null,"base_score":4.1588830833596715,"endowment":4.1588830833596715,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24884780","pmcid":null,"openalex_id":"https://openalex.org/W1987505073","authors":[],"funders":[{"funder_name":"Cancer Research UK","grant_id":"19257","title":null}],"total_grants":1,"fwci":2.9894,"citation_percentile":0.91783036,"influential_citations":0,"citation_trend":[{"year":2014,"count":2},{"year":2015,"count":7},{"year":2016,"count":7},{"year":2017,"count":7},{"year":2018,"count":8},{"year":2019,"count":3},{"year":2020,"count":5},{"year":2021,"count":2},{"year":2022,"count":5},{"year":2023,"count":7},{"year":2024,"count":8},{"year":2025,"count":2}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://doi.org/10.7270/q24q7wjp","host_type":"repository"},{"url":"https://doi.org/10.7270/q24q7wjp","host_type":"repository"},{"url":"https://pubs.acs.org/doi/pdf/10.1021/jm500632s","host_type":"publisher"},{"url":"https://doi.org/10.1021/jm500632s","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24884780","host_type":"repository"},{"url":"http://eprints.gla.ac.uk/197584/","host_type":"journal"},{"url":"http://hdl.handle.net/11858/00-001M-0000-0019-BA15-7","host_type":"repository"}],"fields_of_study":["Protein Kinase Regulation and GTPase Signaling","Neuroscience and Neuropharmacology Research","Receptor Mechanisms and Signaling","Atorvastatin","Benzimidazoles","Binding Sites","Cell Line, Tumor","Computer Simulation","Cyclic Nucleotide Phosphodiesterases, Type 6","Drug Design","Esters","Ethers","Heptanoic Acids","Humans","Kinetics","Models, Molecular","Protein Prenylation","Pyrroles","Stereoisomerism","Structure-Activity Relationship","Thermodynamics","ras Proteins"],"mesh_terms":["Atorvastatin","Benzimidazoles","Binding Sites","Computer Simulation","Esters","Ethers","Heptanoic Acids","Humans","Kinetics","Models, Molecular","Pyrroles","Stereoisomerism","Structure-Activity Relationship","Thermodynamics","Drug Design","Protein Prenylation","ras Proteins","Cell Line, Tumor","Cyclic Nucleotide Phosphodiesterases, Type 6"],"keywords":["Prenylation","Benzimidazole","Chemistry","Small molecule","Cytosol","GTPase","Binding site","Endogeny","Small GTPase","Drug discovery","Signal transduction","Enzyme","Cell biology","Biochemistry","Biology"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T16:44:32.443846Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}