{"doi":"10.1021/jacs.1c04841","title":"Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation","abstract":"Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.","journal":"Journal of the American Chemical Society","year":2021,"id":147846,"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":144,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":462755,"name":"Fanye Meng","orcid":null,"position":1,"is_corresponding":false},{"id":462036,"name":"Kwang‐Su Park","orcid":"0000-0002-1910-3937","position":2,"is_corresponding":false},{"id":337230,"name":"Hyerin Yim","orcid":"0000-0001-5547-1203","position":3,"is_corresponding":false},{"id":628794,"name":"Julia Velez","orcid":"0000-0003-2448-7848","position":4,"is_corresponding":false},{"id":628795,"name":"Prashasti Kumar","orcid":"0000-0002-7974-9238","position":5,"is_corresponding":false},{"id":307162,"name":"Li Wang","orcid":"0000-0001-7415-5599","position":6,"is_corresponding":false},{"id":628796,"name":"Ling Xie","orcid":"0000-0001-8580-0901","position":7,"is_corresponding":false},{"id":462037,"name":"He Chen","orcid":"0000-0001-9644-8202","position":8,"is_corresponding":false},{"id":462753,"name":"Yudao Shen","orcid":null,"position":9,"is_corresponding":false},{"id":628797,"name":"Emily M. Teichman","orcid":"0000-0003-1336-0999","position":10,"is_corresponding":false},{"id":628798,"name":"Dongxu Li","orcid":"0000-0002-9701-5377","position":11,"is_corresponding":false},{"id":247178,"name":"Gang Greg Wang","orcid":"0000-0002-7210-9940","position":12,"is_corresponding":false},{"id":11742,"name":"Xian Chen","orcid":"0000-0002-8358-1247","position":13,"is_corresponding":false},{"id":228876,"name":"H. Ümit Kanıskan","orcid":"0000-0001-5327-832X","position":14,"is_corresponding":false},{"id":228877,"name":"Jian Jin","orcid":"0000-0002-2387-3862","position":15,"is_corresponding":false},{"id":338435,"name":"Jieli Wei","orcid":null,"position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-18T23:42:35.448762Z","pmid":"34520194","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":[]}