{"doi":"10.1021/jacs.3c13448","title":"Proteomic Ligandability Maps of Spirocycle Acrylamide Stereoprobes Identify Covalent ERCC3 Degraders","abstract":"Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe a set of stereo- and regiochemically defined spirocycle acrylamides and the analysis of these electrophilic \"stereoprobes\" in human cancer cells by cysteine-directed ABPP. Despite showing attenuated reactivity compared to structurally related azetidine acrylamide stereoprobes, the spirocycle acrylamides preferentially liganded specific cysteines on diverse protein classes. One compound termed ZL-12A promoted the degradation of the TFIIH helicase ERCC3. Interestingly, ZL-12A reacts with the same cysteine (C342) in ERCC3 as the natural product triptolide, which did not lead to ERCC3 degradation but instead causes collateral loss of RNA polymerases. ZL-12A and triptolide cross-antagonized one another's protein degradation profiles. Finally, we provide evidence that the antihypertension drug spironolactone─previously found to promote ERCC3 degradation through an enigmatic mechanism─also reacts with ERCC3_C342. Our findings thus describe monofunctional degraders of ERCC3 and highlight how covalent ligands targeting the same cysteine can produce strikingly different functional outcomes.","journal":"Journal of the American Chemical Society","year":2024,"id":419458,"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":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"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":337814,"name":"Jarrett R. Remsberg","orcid":"0000-0002-5234-0168","position":1,"is_corresponding":false},{"id":75556,"name":"Haoxin Li","orcid":"0000-0003-4862-0666","position":2,"is_corresponding":false},{"id":854363,"name":"Evert Njomen","orcid":"0000-0002-3508-2638","position":3,"is_corresponding":false},{"id":309922,"name":"Kristen E. DeMeester","orcid":null,"position":4,"is_corresponding":false},{"id":620989,"name":"Yongfeng Tao","orcid":"0000-0001-8884-204X","position":5,"is_corresponding":false},{"id":1034608,"name":"Guoqin Xia","orcid":"0000-0001-7666-9550","position":6,"is_corresponding":false},{"id":576347,"name":"Rachel E. Hayward","orcid":"0000-0002-1080-8244","position":7,"is_corresponding":false},{"id":795872,"name":"Minjin Yoo","orcid":null,"position":8,"is_corresponding":false},{"id":1161954,"name":"Tracey Nguyen","orcid":null,"position":9,"is_corresponding":false},{"id":486535,"name":"Gabriel M. Simon","orcid":"0009-0000-9403-7178","position":10,"is_corresponding":false},{"id":227629,"name":"Stuart L. Schreiber","orcid":"0000-0003-1922-7558","position":11,"is_corresponding":false},{"id":443636,"name":"Bruno Melillo","orcid":"0000-0002-9708-5287","position":12,"is_corresponding":false},{"id":236419,"name":"Benjamin F. Cravatt","orcid":"0000-0001-5330-3492","position":13,"is_corresponding":false},{"id":492207,"name":"Zhonglin Liu","orcid":"0000-0001-6004-7722","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T01:57:14.586331Z","pmid":"38569115","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":[]}