{"doi":"10.3389/fmolb.2020.00081","title":"Structure and Characterization of a Covalent Inhibitor of Src Kinase","abstract":"Unregulated Src activity promotes malignant processes in cancer, but no Src-directed targeted therapies are used clinically, possibly because early Src inhibitors produce off-target effects leading to toxicity. Improved selective Src inhibitors may enable Src-directed therapies. Previously, we reported an irreversible Src inhibitor, DGY-06-116, based on the hybridization of dasatinib and a promiscuous covalent kinase probe SM1-71. Here, we report biochemical and biophysical characterization of this compound. An x-ray co-crystal structure of DGY-06-116: Src shows a covalent interaction with the kinase p-loop and occupancy of the back hydrophobic kinase pocket, explaining its high potency, and selectivity. However, a reversible analog also shows similar potency. Kinetic analysis shows a slow inactivation rate compared to other clinically approved covalent kinase inhibitors, consistent with a need for p-loop movement prior to covalent bond formation. Overall, these results suggest that a strong reversible interaction is required to allow sufficient time for the covalent reaction to occur. Further optimization of the covalent linker may improve the kinetics of covalent bond formation.","journal":"Frontiers in Molecular Biosciences","year":2020,"id":101512,"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":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":228754,"name":"Guangyan Du","orcid":"0000-0002-6413-8741","position":1,"is_corresponding":false},{"id":255570,"name":"Nathaniel J. Henning","orcid":"0000-0003-0504-6481","position":2,"is_corresponding":false},{"id":497054,"name":"Suman Rao","orcid":"0000-0002-5046-0852","position":3,"is_corresponding":false},{"id":453451,"name":"Asim K. Bera","orcid":"0000-0001-9473-2912","position":4,"is_corresponding":false},{"id":226576,"name":"Tinghu Zhang","orcid":"0000-0003-1028-8020","position":5,"is_corresponding":false},{"id":226581,"name":"Nathanael S. Gray","orcid":"0000-0001-5354-7403","position":6,"is_corresponding":false},{"id":363328,"name":"Kenneth D. Westover","orcid":"0000-0003-3653-5923","position":7,"is_corresponding":false},{"id":497053,"name":"Deepak Gurbani","orcid":"0000-0002-0982-7173","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T22:40:22.678835Z","pmid":"32509799","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":[]}