{"doi":"10.1038/s42004-024-01177-4","title":"Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader","abstract":"Abstract Aldo-keto reductase 1C3 (AKR1C3) is a protein upregulated in prostate cancer, hematological malignancies, and other cancers where it contributes to proliferation and chemotherapeutic resistance. Androgen receptor splice variant 7 (ARv7) is the most common mutation of the AR receptor that confers resistance to clinical androgen receptor signalling inhibitors in castration-resistant prostate cancer. AKR1C3 interacts with ARv7 promoting stabilization. Herein we report the discovery of the first-in-class AKR1C3 Proteolysis-Targeting Chimera (PROTAC) degrader. This first-generation degrader potently reduced AKR1C3 expression in 22Rv1 prostate cancer cells with a half-maximal degradation concentration (DC 50 ) of 52 nM. Gratifyingly, concomitant degradation of ARv7 was observed with a DC 50 = 70 nM, along with degradation of the AKR1C3 isoforms AKR1C1 and AKR1C2 to a lesser extent. This compound represents a highly useful chemical tool and a promising strategy for prostate cancer intervention.","journal":"Communications Chemistry","year":2024,"id":433970,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":951165,"name":"Shirisha Jonnalagadda","orcid":"0000-0002-5403-4383","position":1,"is_corresponding":false},{"id":1060134,"name":"Alfie M. Case","orcid":null,"position":2,"is_corresponding":false},{"id":954148,"name":"Maddeboina Krishnaiah","orcid":"0009-0000-4385-9788","position":3,"is_corresponding":false},{"id":629894,"name":"Sravan K. Jonnalagadda","orcid":"0000-0002-2022-7734","position":4,"is_corresponding":false},{"id":1059615,"name":"Louise F. Dow","orcid":"0009-0003-5718-5253","position":5,"is_corresponding":false},{"id":1109064,"name":"Ling Duan","orcid":"0009-0006-3884-0808","position":6,"is_corresponding":false},{"id":482505,"name":"T.M. Penning","orcid":"0000-0002-3937-1066","position":7,"is_corresponding":false},{"id":388255,"name":"Paul C. Trippier","orcid":"0000-0002-4947-5782","position":8,"is_corresponding":false},{"id":589324,"name":"Angelica V. Carmona","orcid":"0000-0001-9722-5254","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T01:59:49.434790Z","pmid":"38684887","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":[]}