{"doi":"10.1021/acschembio.4c00025","title":"Discovery of a Tunable Heterocyclic Electrophile 4-Chloro-pyrazolopyridine That Defines a Unique Subset of Ligandable Cysteines","abstract":"Electrophilic small molecules with novel reactivity are powerful tools that enable activity-based protein profiling and covalent inhibitor discovery. Here, we report a reactive heterocyclic scaffold, 4-chloro-pyrazolopyridine (CPzP) for selective modification of proteins via a nucleophilic aromatic substitution (S N Ar) mechanism. Chemoproteomic profiling reveals that CPzPs engage cysteines within functionally diverse protein sites including ribosomal protein S5 (RPS5), inosine monophosphate dehydrogenase 2 (IMPDH2), and heat shock protein 60 (HSP60). Through the optimization of appended recognition elements, we demonstrate the utility of CPzP for covalent inhibition of prolyl endopeptidase (PREP) by targeting a noncatalytic active-site cysteine. This study suggests that the proteome reactivity of CPzPs can be modulated by both electronic and steric features of the ring system, providing a new tunable electrophile for applications in chemoproteomics and covalent inhibitor design.","journal":"ACS Chemical Biology","year":2024,"id":444495,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"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":1043017,"name":"David P. Byun","orcid":"0000-0002-9513-804X","position":1,"is_corresponding":false},{"id":1259977,"name":"Kalyani Thakur","orcid":"0000-0001-8856-3278","position":2,"is_corresponding":false},{"id":610010,"name":"Jennifer M. Ritchie","orcid":"0000-0002-1244-3082","position":3,"is_corresponding":false},{"id":324004,"name":"Yixin Xie","orcid":"0000-0002-7274-7731","position":4,"is_corresponding":false},{"id":353426,"name":"Ronald J. Holewinski","orcid":"0000-0002-3337-3984","position":5,"is_corresponding":false},{"id":511610,"name":"Kiall F. Suazo","orcid":"0000-0002-0803-8332","position":6,"is_corresponding":false},{"id":408081,"name":"Mckayla Stevens","orcid":null,"position":7,"is_corresponding":false},{"id":946562,"name":"Hope Liechty","orcid":null,"position":8,"is_corresponding":false},{"id":864182,"name":"Ravichandra Tagirasa","orcid":"0000-0002-9839-3214","position":9,"is_corresponding":false},{"id":339807,"name":"Yihang Jing","orcid":"0000-0002-9188-9479","position":10,"is_corresponding":false},{"id":276014,"name":"Þorkell Andrésson","orcid":"0000-0002-9545-2450","position":11,"is_corresponding":false},{"id":406885,"name":"Steven M. Johnson","orcid":"0000-0001-7254-4128","position":12,"is_corresponding":false},{"id":582286,"name":"Euna Yoo","orcid":"0000-0001-5982-1979","position":13,"is_corresponding":false},{"id":1043019,"name":"Hong‐Rae Kim","orcid":"0000-0001-5361-7168","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:01:37.886033Z","pmid":"38629450","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":[]}