{"id":"https://openalex.org/W4417128205","doi":"https://doi.org/10.1101/gad.352916.125","title":"Combinatorial use of VHL and KEAP1 PROTACs reveals unexpected synergy and hook effect relief","display_name":"Combinatorial use of VHL and KEAP1 PROTACs reveals unexpected synergy and hook effect relief","publication_year":2025,"publication_date":"2025-12-08","ids":{"openalex":"https://openalex.org/W4417128205","doi":"https://doi.org/10.1101/gad.352916.125","pmid":"https://pubmed.ncbi.nlm.nih.gov/41360670","pmcid":"https://www.ncbi.nlm.nih.gov/pmc/articles/12951757"},"language":"en","primary_location":{"id":"doi:10.1101/gad.352916.125","doi":"https://doi.org/10.1101/gad.352916.125","is_oa":true,"landing_page_url":"https://doi.org/10.1101/gad.352916.125","pdf_url":null,"source":{"id":"https://openalex.org/S168778273","display_name":"Genes & Development","issn_l":"0890-9369","issn":["0890-9369","1549-5477"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["cwts-core","dongbi-a","doyens","jufo-3","ki-jl-2","medline","norway-2","poland-200","russia-white-list-1"],"host_organization":"https://openalex.org/P4310315909","host_organization_name":"Cold Spring Harbor Laboratory Press","host_organization_lineage":["https://openalex.org/P4310315909"],"host_organization_lineage_names":["Cold Spring Harbor Laboratory Press"],"type":"journal"},"license":"cc-by-nc","license_id":"https://openalex.org/licenses/cc-by-nc","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Genes & Development","raw_type":"journal-article"},"volume":null,"type":"preprint","indexed_in":["crossref","pubmed"],"open_access":{"is_oa":true,"oa_status":"hybrid","oa_url":"https://doi.org/10.1101/gad.352916.125","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5000255838","display_name":"Sehbanul Islam","orcid":"https://orcid.org/0000-0003-2686-2787","observed_orcids":["https://orcid.org/0000-0003-2686-2787"]},"institutions":[{"id":"https://openalex.org/I79576946","display_name":"University of Pennsylvania","ror":"https://ror.org/00b30xv10","country_code":"US","type":"education","lineage":["https://openalex.org/I79576946"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Sehbanul Islam","raw_affiliation_strings":["Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA"],"raw_orcid":"https://orcid.org/0000-0003-2686-2787","affiliations":[{"raw_affiliation_string":"Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA","institution_ids":["https://openalex.org/I79576946"]}]},{"author_position":"middle","author":{"id":null,"display_name":"Haihong Jin","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Haihong Jin","raw_affiliation_strings":["SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA","institution_ids":[]}]},{"author_position":"middle","author":{"id":null,"display_name":"Dong Liu","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Dong Liu","raw_affiliation_strings":["SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5106889064","display_name":"Dan L\u00fc","orcid":"https://orcid.org/0000-0002-9657-1574","observed_orcids":["https://orcid.org/0000-0002-9657-1574"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Dan Lu","raw_affiliation_strings":["SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5012459905","display_name":"Yunkai Zhang","orcid":"https://orcid.org/0000-0003-2490-5501","observed_orcids":["https://orcid.org/0000-0003-2490-5501","https://orcid.org/0009-0007-4932-6270"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Yunkai Zhang","raw_affiliation_strings":["SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5073588112","display_name":"Eric T. Christenson","orcid":"https://orcid.org/0000-0001-7463-7694","observed_orcids":["https://orcid.org/0000-0001-7463-7694"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Eric Christenson","raw_affiliation_strings":["SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA","institution_ids":[]}]},{"author_position":"middle","author":{"id":null,"display_name":"Renxu Chang","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I79576946","display_name":"University of Pennsylvania","ror":"https://ror.org/00b30xv10","country_code":"US","type":"education","lineage":["https://openalex.org/I79576946"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Renxu Chang","raw_affiliation_strings":["Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA","institution_ids":["https://openalex.org/I79576946"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5081592097","display_name":"Joel Austin","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Joel Austin","raw_affiliation_strings":["SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5052725024","display_name":"Anneliese M. Faustino","orcid":"https://orcid.org/0000-0003-1743-9186","observed_orcids":["https://orcid.org/0000-0003-1743-9186"]},"institutions":[{"id":"https://openalex.org/I102322052","display_name":"The Wistar Institute","ror":"https://ror.org/04wncat98","country_code":"US","type":"facility","lineage":["https://openalex.org/I102322052"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Anneliese Faustino","raw_affiliation_strings":["Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA","institution_ids":["https://openalex.org/I102322052"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5104234069","display_name":"Thomas Beer","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I102322052","display_name":"The Wistar Institute","ror":"https://ror.org/04wncat98","country_code":"US","type":"facility","lineage":["https://openalex.org/I102322052"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Thomas Beer","raw_affiliation_strings":["Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA","institution_ids":["https://openalex.org/I102322052"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5062036183","display_name":"Hsin\u2010Yao Tang","orcid":"https://orcid.org/0000-0003-1838-018X","observed_orcids":["https://orcid.org/0000-0003-1838-018X"]},"institutions":[{"id":"https://openalex.org/I102322052","display_name":"The Wistar Institute","ror":"https://ror.org/04wncat98","country_code":"US","type":"facility","lineage":["https://openalex.org/I102322052"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Hsin-Yao Tang","raw_affiliation_strings":["Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA","institution_ids":["https://openalex.org/I102322052"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5100727465","display_name":"Lan Ji Huang","orcid":"https://orcid.org/0000-0001-9594-4722","observed_orcids":["https://orcid.org/0000-0001-9594-4722"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Lan Huang","raw_affiliation_strings":["SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5075372173","display_name":"James R. Tonra","orcid":"https://orcid.org/0000-0003-3284-7516","observed_orcids":["https://orcid.org/0000-0003-3284-7516"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"James R. Tonra","raw_affiliation_strings":["SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"SEED Therapeutics, Inc., King of Prussia, Pennsylvania 19406, USA","institution_ids":[]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5040917213","display_name":"Luca Busino","orcid":"https://orcid.org/0000-0001-6758-9276","observed_orcids":["https://orcid.org/0000-0001-6758-9276"]},"institutions":[{"id":"https://openalex.org/I79576946","display_name":"University of Pennsylvania","ror":"https://ror.org/00b30xv10","country_code":"US","type":"education","lineage":["https://openalex.org/I79576946"]}],"countries":["US"],"is_corresponding":true,"raw_author_name":"Luca Busino","raw_affiliation_strings":["Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;","Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; businol@upenn.edu"],"raw_orcid":"https://orcid.org/0000-0001-6758-9276","affiliations":[{"raw_affiliation_string":"Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;","institution_ids":["https://openalex.org/I79576946"]},{"raw_affiliation_string":"Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; businol@upenn.edu","institution_ids":["https://openalex.org/I79576946"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":2,"corresponding_author_ids":["https://openalex.org/A5040917213"],"corresponding_institution_ids":["https://openalex.org/I79576946"],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":false,"cited_by_count":5,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":"40","issue":"5-6","first_page":"308","last_page":"318"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T12534","display_name":"Protein Degradation and Inhibitors","score":1.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T12534","display_name":"Protein Degradation and Inhibitors","score":1.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11041","display_name":"Ubiquitin and proteasome pathways","score":0.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10911","display_name":"Chemical Synthesis and Analysis","score":0.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/protacs","display_name":"PROTACs","score":0.9399999976158142},{"id":"https://openalex.org/keywords/vhl","display_name":"VHL","score":0.6430000066757202},{"id":"https://openalex.org/keywords/keap1","display_name":"Keap1","score":1.0},{"id":"https://openalex.org/keywords/hook-effect","display_name":"hook effect","score":0.9700000286102295},{"id":"https://openalex.org/keywords/kras-g12d","display_name":"KRAS G12D","score":0.8999999761581421},{"id":"https://openalex.org/keywords/androgen-receptor","display_name":"androgen receptor","score":0.9860000014305115},{"id":"https://openalex.org/keywords/ubiquitin-chain-elongation","display_name":"ubiquitin chain elongation","score":0.9539999961853027},{"id":"https://openalex.org/keywords/protein-degradation","display_name":"protein degradation","score":0.8410000205039978}],"concepts":[{"id":"https://openalex.org/C134459356","wikidata":"https://www.wikidata.org/wiki/Q4274835","display_name":"Ubiquitin ligase","level":4,"score":0.8799999952316284},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.8131999969482422},{"id":"https://openalex.org/C25602115","wikidata":"https://www.wikidata.org/wiki/Q407111","display_name":"Ubiquitin","level":3,"score":0.8001999855041504},{"id":"https://openalex.org/C95444343","wikidata":"https://www.wikidata.org/wiki/Q7141","display_name":"Cell biology","level":1,"score":0.5651000142097473},{"id":"https://openalex.org/C2908868211","wikidata":"https://www.wikidata.org/wiki/Q4274835","display_name":"Ubiquitin-Protein Ligases","level":5,"score":0.4724000096321106},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.4131999909877777},{"id":"https://openalex.org/C2992195973","wikidata":"https://www.wikidata.org/wiki/Q33123","display_name":"Protein degradation","level":2,"score":0.40790000557899475},{"id":"https://openalex.org/C89611455","wikidata":"https://www.wikidata.org/wiki/Q6804646","display_name":"Mechanism (biology)","level":2,"score":0.38449999690055847},{"id":"https://openalex.org/C175114707","wikidata":"https://www.wikidata.org/wiki/Q408483","display_name":"DNA ligase","level":3,"score":0.37880000472068787},{"id":"https://openalex.org/C61367390","wikidata":"https://www.wikidata.org/wiki/Q416601","display_name":"Androgen receptor","level":4,"score":0.3587000072002411},{"id":"https://openalex.org/C27740335","wikidata":"https://www.wikidata.org/wiki/Q14878333","display_name":"Proteasome","level":2,"score":0.35359999537467957},{"id":"https://openalex.org/C102658986","wikidata":"https://www.wikidata.org/wiki/Q5266092","display_name":"Deubiquitinating enzyme","level":4,"score":0.3513999879360199},{"id":"https://openalex.org/C2776192174","wikidata":"https://www.wikidata.org/wiki/Q18028978","display_name":"Mdm2","level":3,"score":0.34459999203681946},{"id":"https://openalex.org/C2776529522","wikidata":"https://www.wikidata.org/wiki/Q18034700","display_name":"KEAP1","level":4,"score":0.34310001134872437},{"id":"https://openalex.org/C174510640","wikidata":"https://www.wikidata.org/wiki/Q489618","display_name":"HEK 293 cells","level":3,"score":0.31869998574256897},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.3059000074863434},{"id":"https://openalex.org/C60644358","wikidata":"https://www.wikidata.org/wiki/Q128570","display_name":"Bioinformatics","level":1,"score":0.29670000076293945},{"id":"https://openalex.org/C182561583","wikidata":"https://www.wikidata.org/wiki/Q7876535","display_name":"Ubiquitin-conjugating enzyme","level":5,"score":0.29100000858306885},{"id":"https://openalex.org/C74187038","wikidata":"https://www.wikidata.org/wiki/Q1418791","display_name":"Drug discovery","level":2,"score":0.2612000107765198},{"id":"https://openalex.org/C502942594","wikidata":"https://www.wikidata.org/wiki/Q3421914","display_name":"Cancer research","level":1,"score":0.2526000142097473}],"mesh":[{"descriptor_ui":"D000072019","descriptor_name":"Kelch-Like ECH-Associated Protein 1","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D000094243","descriptor_name":"Proteolysis Targeting Chimera","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D006801","descriptor_name":"Humans","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D011944","descriptor_name":"Receptors, Androgen","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D016283","descriptor_name":"Proto-Oncogene Proteins p21(ras)","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D044767","descriptor_name":"Ubiquitin-Protein Ligases","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D045744","descriptor_name":"Cell Line, Tumor","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D051794","descriptor_name":"Von Hippel-Lindau Tumor Suppressor Protein","qualifier_ui":"Q000235","qualifier_name":"genetics","is_major_topic":true},{"descriptor_ui":"D051794","descriptor_name":"Von Hippel-Lindau Tumor Suppressor Protein","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D054875","descriptor_name":"Ubiquitination","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D059748","descriptor_name":"Proteolysis","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true}],"locations_count":3,"locations":[{"id":"doi:10.1101/gad.352916.125","doi":"https://doi.org/10.1101/gad.352916.125","is_oa":true,"landing_page_url":"https://doi.org/10.1101/gad.352916.125","pdf_url":null,"source":{"id":"https://openalex.org/S168778273","display_name":"Genes & Development","issn_l":"0890-9369","issn":["0890-9369","1549-5477"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["cwts-core","dongbi-a","doyens","jufo-3","ki-jl-2","medline","norway-2","poland-200","russia-white-list-1"],"host_organization":"https://openalex.org/P4310315909","host_organization_name":"Cold Spring Harbor Laboratory Press","host_organization_lineage":["https://openalex.org/P4310315909"],"host_organization_lineage_names":["Cold Spring Harbor Laboratory Press"],"type":"journal"},"license":"cc-by-nc","license_id":"https://openalex.org/licenses/cc-by-nc","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Genes & Development","raw_type":"journal-article"},{"id":"pmid:41360670","doi":null,"is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/41360670","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Genes & development","raw_type":"Journal Article"},{"id":"pmh:oai:pubmedcentral.nih.gov:12951757","doi":null,"is_oa":true,"landing_page_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12951757/","pdf_url":null,"source":{"id":"https://openalex.org/S2764455111","display_name":"PubMed Central","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc","license_id":"https://openalex.org/licenses/cc-by-nc","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Genes Dev","raw_type":"Text"}],"best_oa_location":{"id":"doi:10.1101/gad.352916.125","doi":"https://doi.org/10.1101/gad.352916.125","is_oa":true,"landing_page_url":"https://doi.org/10.1101/gad.352916.125","pdf_url":null,"source":{"id":"https://openalex.org/S168778273","display_name":"Genes & Development","issn_l":"0890-9369","issn":["0890-9369","1549-5477"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["cwts-core","dongbi-a","doyens","jufo-3","ki-jl-2","medline","norway-2","poland-200","russia-white-list-1"],"host_organization":"https://openalex.org/P4310315909","host_organization_name":"Cold Spring Harbor Laboratory Press","host_organization_lineage":["https://openalex.org/P4310315909"],"host_organization_lineage_names":["Cold Spring Harbor Laboratory Press"],"type":"journal"},"license":"cc-by-nc","license_id":"https://openalex.org/licenses/cc-by-nc","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Genes & Development","raw_type":"journal-article"},"sustainable_development_goals":[{"score":0.7246000170707703,"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being"}],"study_designs":[],"awards":[{"id":"https://openalex.org/G120344028","display_name":null,"funder_award_id":"RSG-19-199-01","funder_id":"https://openalex.org/F4320306095","funder_display_name":"American Cancer Society"},{"id":"https://openalex.org/G1732014367","display_name":null,"funder_award_id":"R01-HL159175","funder_id":"https://openalex.org/F4320337338","funder_display_name":"National Heart, Lung, and Blood Institute"},{"id":"https://openalex.org/G1880492126","display_name":"Regulation of emergency hematopoiesis by the ubiquitin-proteasome system","funder_award_id":"5r01hl159175-04","funder_id":"https://openalex.org/F4320332161","funder_display_name":"National Institutes of Health"},{"id":"https://openalex.org/G8297855124","display_name":"Assessing the Therapeutic Potential of PARPi and PROTACs in BRCA-Mutated Cancers","funder_award_id":"PF-24-1320981-01-ET","funder_id":"https://openalex.org/F4320306095","funder_display_name":"American Cancer Society"},{"id":"https://openalex.org/G9000859306","display_name":"Advancing Cancer Research through Comprehensive Proteomics and Metabolomics Analyses","funder_award_id":"R50CA221838","funder_id":"https://openalex.org/F4320337351","funder_display_name":"National Cancer Institute"},{"id":"https://openalex.org/G9000868875","display_name":"Role of KLHL6 inactivation in mature B-cell malignancies","funder_award_id":"R01CA207513","funder_id":"https://openalex.org/F4320337351","funder_display_name":"National Cancer Institute"},{"id":"https://openalex.org/G9000906427","display_name":"Consolidated Basic Cancer Research Program","funder_award_id":"P30CA010815","funder_id":"https://openalex.org/F4320337351","funder_display_name":"National Cancer Institute"},{"id":"https://openalex.org/G915722980","display_name":null,"funder_award_id":"R50 CA221838","funder_id":"https://openalex.org/F4320306095","funder_display_name":"American Cancer Society"}],"funders":[{"id":"https://openalex.org/F4320306095","display_name":"American Cancer Society","ror":"https://ror.org/02e463172"},{"id":"https://openalex.org/F4320332161","display_name":"National Institutes of Health","ror":"https://ror.org/01cwqze88"},{"id":"https://openalex.org/F4320337338","display_name":"National Heart, Lung, and Blood Institute","ror":"https://ror.org/012pb6c26"},{"id":"https://openalex.org/F4320337351","display_name":"National Cancer Institute","ror":"https://ror.org/040gcmg81"}],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":27,"referenced_works":["https://openalex.org/W1488181101","https://openalex.org/W1512690422","https://openalex.org/W1565539350","https://openalex.org/W1953264505","https://openalex.org/W1981916517","https://openalex.org/W1982855701","https://openalex.org/W1988031203","https://openalex.org/W1993735775","https://openalex.org/W2015345028","https://openalex.org/W2050389860","https://openalex.org/W2064293531","https://openalex.org/W2068412287","https://openalex.org/W2068455168","https://openalex.org/W2076194625","https://openalex.org/W2124560610","https://openalex.org/W2147291971","https://openalex.org/W2623602792","https://openalex.org/W2636904491","https://openalex.org/W2781383440","https://openalex.org/W2883077013","https://openalex.org/W2994492843","https://openalex.org/W3002432707","https://openalex.org/W3006502081","https://openalex.org/W3010955175","https://openalex.org/W4200173198","https://openalex.org/W4205933836","https://openalex.org/W4294786865"],"related_works":["https://openalex.org/W4409690102","https://openalex.org/W7133870468","https://openalex.org/W4404825860","https://openalex.org/W2917115789","https://openalex.org/W2909835348","https://openalex.org/W4383676245","https://openalex.org/W4402654355","https://openalex.org/W7221567034","https://openalex.org/W4389702496","https://openalex.org/W4398200663"],"abstract_inverted_index":{"Proteolysis-targeting":[0],"chimeras":[1],"(PROTACs)":[2],"are":[3,21],"bifunctional":[4],"molecules":[5],"bridging":[6],"a":[7,33,52,87,92],"protein":[8],"with":[9],"an":[10],"E3":[11,59],"ubiquitin":[12,76],"ligase,":[13],"promoting":[14,75],"its":[15],"ubiquitylation":[16],"and":[17,29,64,70,79],"degradation.":[18],"However,":[19],"PROTACs":[20],"not":[22],"without":[23],"limitations,":[24],"including":[25],"suboptimal":[26],"target":[27],"degradation":[28],"the":[30,82],"\"hook":[31],"effect,\"":[32],"phenomenon":[34],"where":[35],"high":[36],"PROTAC":[37],"concentrations":[38],"reduce":[39],"efficacy":[40],"due":[41],"to":[42,66],"inactive":[43],"binary":[44],"complex":[45],"formation.":[46],"In":[47,85],"this":[48],"study,":[49],"we":[50],"introduce":[51],"novel":[53],"dual-PROTAC":[54],"strategy":[55],"utilizing":[56],"two":[57],"distinct":[58],"ligases,":[60],"such":[61],"as":[62],"KEAP1":[63],"VHL,":[65],"synergistically":[67],"degrade":[68],"KRAS(G12D)":[69],"androgen":[71],"receptor":[72],"(AR)":[73],"by":[74],"chain":[77],"elongation":[78],"also":[80],"mitigating":[81],"hook":[83],"effect.":[84],"conclusion,":[86],"dual-E3":[88],"ligase":[89],"approach":[90],"represents":[91],"promising":[93],"avenue":[94],"for":[95],"optimizing":[96],"PROTAC-based":[97],"therapeutics.":[98]},"counts_by_year":[{"year":2026,"cited_by_count":5}],"updated_date":"2026-10-31T12:09:11.096373","created_date":"2025-12-08T00:00:00"}