{"doi":"10.26434/chemrxiv.13299149","title":"Novel Inhibitors of Eukaryotic Elongation Factor 2 Kinase: In Silico, Synthesis, and in Vitro Studies","abstract":"<p>Eukaryotic elongation factor 2 kinase (eEF2K) is an unusual alpha kinase whose expression is highly upregulated in various cancers and contributes to tumor growth, metastasis, and progression. More importantly, expression of eEF2K is associated with poor clinical outcome and shorter patient survival triple negative breast cancer (TNBC). Therefore, eEF2K is an emerging molecular target for development of novel targeted therapeutics and precision medicine in solid cancers. However, currently potent, and specific inhibitors of eEF2K are not available for clinical translation. In the current study, we investigated the effects of various newly designed and synthesized a series of compounds with coumarin scaffold substitutions in inhibiting eEF2K activity using <i>in silico </i>approaches and <i>in vitro </i>studies in TNBC cells. We utilized an amide substitution at 3-position on the coumarin ring with their pharmacologically active groups containing pyrrolidine, piperidine, morpholine and piperazine groups with –(CH<sub>2</sub>)<sub>2</sub>– bridged for aliphatic amides. To evaluate substituent effects on coumarin scaffold, boronic acid pinacol ester and boronic acids on phenyl rings were investigated using <i>in silico</i> and <i>in vitro</i> analyses. Due to their ability to form covalent binding to the target enzyme, we investigated the effects of boron containing groups on functionalized coumarin ring (3 compounds) and designed novel aliphatic and aromatic derivatives of coumarin scaffolds (10 compounds) and phenyl ring with boron groups <b>(</b>4 compounds<b>)</b>. <i>In silico</i> analysis and molecular docking studies were performed using the Glide/SP module of Maestro molecular modeling package. According to obtained results, structure activity relationship (SAR) was carried out. Among the newly designed, synthesized, and tested compounds, our <i>in vitro</i> findings revealed that several compounds displayed a highly effective eEF2K inhibition at submicromolar concentration in<i> in vitro </i>breast cancer cells. In conclusion, we identified novel eEF2K inhibitors as promising anticancer drug substance candidates which should be further evaluated by <i>in vivo</i> studies, preclinical and clinical studies.</p><br>","journal":"ChemRxiv","year":2020,"id":128164,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"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":577783,"name":"Serdar Durdağı","orcid":"0000-0002-0426-0905","position":1,"is_corresponding":false},{"id":561088,"name":"Nermin Kahraman","orcid":null,"position":2,"is_corresponding":false},{"id":578250,"name":"Tuğçe Nur Uslu","orcid":null,"position":3,"is_corresponding":false},{"id":577784,"name":"Hakan Kandemir","orcid":"0000-0002-7347-2223","position":4,"is_corresponding":false},{"id":577785,"name":"Esen Bellur Atıcı","orcid":"0000-0002-4093-441X","position":5,"is_corresponding":false},{"id":578886,"name":"Bülent ÖZPOLAT","orcid":null,"position":6,"is_corresponding":false},{"id":577786,"name":"Mehmet Ay","orcid":"0000-0002-1095-1614","position":7,"is_corresponding":false},{"id":577782,"name":"Ferah Cömert Önder","orcid":"0000-0002-4037-1979","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:15:38.879956Z","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":[]}