{"doi":"10.1002/anie.202114813","title":"Exploring Unconventional SAM Analogues To Build Cell‐Potent Bisubstrate Inhibitors for Nicotinamide <i>N</i>‐Methyltransferase","abstract":"Abstract Nicotinamide N ‐methyltransferase (NNMT) methylates nicotinamide and has been associated with various diseases. Herein, we report the first cell‐potent NNMT bisubstrate inhibitor II399 , demonstrating a K i of 5.9 nM in a biochemical assay and a cellular IC 50 value of 1.9 μM. The inhibition mechanism and cocrystal structure confirmed II399 engages both the substrate and cofactor binding pockets. Computational modeling and binding data reveal a balancing act between enthalpic and entropic components that lead to II399′ s low nM binding affinity. Notably, II399 is 1 000‐fold more selective for NNMT than closely related methyltransferases. We expect that II399 would serve as a valuable probe to elucidate NNMT biology. Furthermore, this strategy provides the first case of introducing unconventional SAM mimics, which can be adopted to develop cell‐potent inhibitors for other SAM‐dependent methyltransferases.","journal":"Angewandte Chemie International Edition","year":2022,"id":271437,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9445,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":479022,"name":"Jonah Z. Vilseck","orcid":"0000-0001-7076-8996","position":1,"is_corresponding":false},{"id":492824,"name":"Ravi Yadav","orcid":"0000-0003-2879-0465","position":2,"is_corresponding":false},{"id":352782,"name":"Nicholas Noinaj","orcid":"0000-0001-6361-2336","position":3,"is_corresponding":false},{"id":114878,"name":"Rong Huang","orcid":"0000-0002-1477-3165","position":4,"is_corresponding":false},{"id":506173,"name":"Iredia D. Iyamu","orcid":"0000-0003-1337-1188","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T00:27:39.717534Z","pmid":"35134268","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":[]}