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These compounds may serve as starting points for further development into an unprecedented new class of kidney cancer drugs. The approach described herein may also serve as a blueprint for developing agents to correct destabilized mutations underlying other human diseases.</jats:p>","journal":null,"year":null,"id":615466,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"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":1586375,"name":"Christopher S Parry","orcid":null,"position":1,"is_corresponding":false},{"id":1586376,"name":"Sven A Miller","orcid":null,"position":2,"is_corresponding":false},{"id":486940,"name":"Shipra Malhotra","orcid":"0000-0002-2234-191X","position":3,"is_corresponding":false},{"id":1586377,"name":"Glenn A Doyle","orcid":null,"position":4,"is_corresponding":false},{"id":1586378,"name":"Ezra Shimabenga","orcid":null,"position":5,"is_corresponding":false},{"id":1586379,"name":"Mashhura Nurilloeva","orcid":null,"position":6,"is_corresponding":false},{"id":1069506,"name":"Elena Bondarenko","orcid":"0000-0002-5009-0863","position":7,"is_corresponding":false},{"id":1586380,"name":"Grigorii V Andrianov","orcid":null,"position":8,"is_corresponding":false},{"id":1586381,"name":"Wayne Childers","orcid":null,"position":9,"is_corresponding":false},{"id":1586382,"name":"Benjamin E Blass","orcid":null,"position":10,"is_corresponding":false},{"id":1586383,"name":"Petr B Makhov","orcid":null,"position":11,"is_corresponding":false},{"id":1586384,"name":"Johnathan R Whetstine","orcid":null,"position":12,"is_corresponding":false},{"id":1586385,"name":"Margie L Clapper","orcid":null,"position":13,"is_corresponding":false},{"id":1586386,"name":"Erica A Golemis","orcid":null,"position":14,"is_corresponding":false},{"id":259373,"name":"John Karanicolas","orcid":"0000-0003-0300-726X","position":15,"is_corresponding":false},{"id":1586374,"name":"Mariam Ahmed Fouad","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Rescuing the Function of Missense-Mutated Tumor Suppressor VHL using Stabilizing Small Molecules","abstract":"<jats:p>Somatic mutations in the VHL gene, coupled with VHL loss of heterozygosity, drive sporadic clear cell renal cell carcinoma (ccRCC). From structural considerations, we hypothesized that certain mutations in the VHL gene thermodynamically destabilize the folded protein product; these mutations would increase the ratio of unfolded:folded pVHL, and thus cause loss of function. To test this, we used computational structure-based screening followed by biophysical characterization and cellular assays to identify small molecules that bind to the folded (native) conformation of pVHL and stabilize it. These studies led to creation of an agent, CP4.29, that stabilized the native folded structure of mutant pVHL, that restores wild-type pVHL activities to cells that harbor mutant VHL. These compounds may serve as starting points for further development into an unprecedented new class of kidney cancer drugs. The approach described herein may also serve as a blueprint for developing agents to correct destabilized mutations underlying other human diseases.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19767382","pmcid":null,"openalex_id":"https://openalex.org/W7135036054","authors":[],"funders":[{"funder_name":"DOD | MHS | CDMRP | DOD Peer Reviewed Cancer Research Program","grant_id":"W81XWH-20-1-0844","title":null},{"funder_name":"HHS | NIH | National Institute of General Medical Sciences","grant_id":"R01GM112736","title":null},{"funder_name":"HHS | NIH | National Cancer Institute","grant_id":"P30CA006927","title":null},{"funder_name":"HHS | NIH | National Cancer Institute","grant_id":"U54CA221705","title":null},{"funder_name":"National Science Foundation","grant_id":"1548562","title":null},{"funder_name":"HHS | NIH | National Institute of General Medical Sciences","grant_id":"R01GM141513","title":null}],"total_grants":6,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://elifesciences.org/reviewed-preprints/110305v1.pdf","host_type":"journal"},{"url":"https://elifesciences.org/reviewed-preprints/110305v1.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/preprints/110305/elife-preprint-110305-v1.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/preprints/110305/elife-preprint-110305-v1.xml","host_type":"publisher"},{"url":"https://elifesciences.org/reviewed-preprints/110305v1/pdf","host_type":"publisher"},{"url":"https://doi.org/10.7554/elife.110305.1","host_type":"journal"}],"fields_of_study":["Renal cell carcinoma treatment","Renal and related cancers","Cancer, Hypoxia, and Metabolism"],"mesh_terms":[],"keywords":["Small molecule","Suppressor","Mutant","Mutation","Function (biology)","Loss function","HEK 293 cells","Tumor suppressor gene","Gene"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T20:06:11.833024Z","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":[]}