{"doi":"10.1101/2021.04.13.439666","title":"Chemoproteomic study uncovers HemK2/KMT9 as a new target for NTMT1 bisubstrate inhibitors","abstract":"Abstract Understanding the selectivity of methyltransferase inhibitors is important to dissect the functions of each methyltransferase target. From this perspective, here we report a chemoproteomic study to profile the selectivity of a potent protein N-terminal methyltransferase 1 (NTMT1) bisubstrate inhibitor NAH-C3-GPKK ( K i, app = 7±1 nM) in endogenous proteomes. First, we describe the rational design, synthesis, and biochemical characterization of a new chemical probe 6 , a biotinylated analogue of NAH-C3-GPKK. Next, we systematically analyze protein networks that may selectively interact with the biotinylated probe 6 in concert with the competitor NAH-C3-GPKK. Besides NTMT1, the designated NTMT1 bisubstrate inhibitor NAH-C3-GPKK was found to also potently inhibit a methyltransferase complex HemK2-Trm112 (also known as KMT9-Trm112), highlighting the importance of systematic selectivity profiling. Furthermore, this is the first potent inhibitor for HemK2/KMT9 reported to date. Thus, our studies lay the foundation for future efforts towards the development of selective inhibitors for NTMT1 and HemK2/KMT9. TOC","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225488,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"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":703832,"name":"Ying Meng","orcid":"0000-0002-1165-9009","position":1,"is_corresponding":false},{"id":647919,"name":"Dan Yu","orcid":"0000-0002-3112-2292","position":2,"is_corresponding":false},{"id":352782,"name":"Nicholas Noinaj","orcid":"0000-0001-6361-2336","position":3,"is_corresponding":false},{"id":356553,"name":"Xiaodong Cheng","orcid":"0000-0002-6967-6362","position":4,"is_corresponding":false},{"id":114878,"name":"Rong Huang","orcid":"0000-0002-1477-3165","position":5,"is_corresponding":false},{"id":497932,"name":"Dongxing Chen","orcid":"0000-0003-0046-9741","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:26.581453Z","pmid":null,"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":[]}