{"doi":"10.1021/jacs.1c00451","title":"Cancer Selective Target Degradation by Folate-Caged PROTACs","abstract":"PROTACs (proteolysis targeting chimeras) are an emerging class of promising therapeutic modalities that degrade intracellular protein targets by hijacking the cellular ubiquitin-proteasome system. However, potential toxicity of PROTACs in normal cells due to the off-tissue on-target degradation effect limits their clinical applications. Precise control of a PROTAC's on-target degradation activity in a tissue-selective manner could minimize potential toxicity/side-effects. To this end, we developed a cancer cell selective delivery strategy for PROTACs by conjugating a folate group to a ligand of the VHL E3 ubiquitin ligase, to achieve targeted degradation of proteins of interest (POIs) in cancer cells versus noncancerous normal cells. We show that our folate-PROTACs, including BRD PROTAC (folate-ARV-771), MEK PROTAC (folate-MS432), and ALK PROTAC (folate-MS99), are capable of degrading BRDs, MEKs, and ALK, respectively, in a folate receptor-dependent manner in cancer cells. This design provides a generalizable platform for PROTACs to achieve selective degradation of POIs in cancer cells.","journal":"Journal of the American Chemical Society","year":2021,"id":145900,"datarank":8.40467111562494,"base_score":5.680172609017068,"endowment":5.680172609017068,"self_citation_contribution":0.8520258913525602,"citation_network_contribution":7.5526452242723785,"self_endowment_contribution":0.8520258913525602,"citer_contribution":7.5526452242723785,"corpus_percentile":null,"corpus_rank":null,"citation_count":292,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"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":462037,"name":"He Chen","orcid":"0000-0001-9644-8202","position":1,"is_corresponding":false},{"id":451732,"name":"Yi Liu","orcid":"0000-0002-4106-3484","position":2,"is_corresponding":false},{"id":462753,"name":"Yudao Shen","orcid":null,"position":3,"is_corresponding":false},{"id":462755,"name":"Fanye Meng","orcid":null,"position":4,"is_corresponding":false},{"id":228876,"name":"H. Ümit Kanıskan","orcid":"0000-0001-5327-832X","position":5,"is_corresponding":false},{"id":228877,"name":"Jian Jin","orcid":"0000-0002-2387-3862","position":6,"is_corresponding":false},{"id":231158,"name":"Wenyi Wei","orcid":"0000-0003-0512-3811","position":7,"is_corresponding":false},{"id":272392,"name":"Jing Liu","orcid":"0000-0002-3113-4015","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:42:12.871665Z","pmid":"33970635","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":[]}