{"doi":"10.1101/2025.10.22.683941","title":"Identification and Validation of an inhibitor of the protein kinases PIM and DYRK","abstract":"Fermented wheat germ extract (FWGE), a nutraceutical with reported anticancer properties, contains numerous biologically active molecules, but its precise therapeutic constituents remain unclear. In this study, we identify and characterize a novel small-molecule inhibitor, CSH-4044, isolated from FWGE. Through preparative HPLC and structural elucidation via X-ray crystallography, CSH-4044 was revealed to be a unique benzothiazole compound. Kinase profiling demonstrated its high specificity toward the PIM and DYRK families of protein kinases. We determined the co-crystal structure of CSH-4044 bound to PIM1, revealing ATP-competitive binding, and critical hydrophobic and hydrogen-bonding interactions. A chemically synthesized version of CSH-4044 mirrored the activity of the natural product, confirming structural integrity and biological equivalence. Functionally, CSH-4044 suppressed PIM3-driven BAD phosphorylation in pancreatic cancer cells and reduced DYRK1A-mediated Tau phosphorylation in neuronal cells. Our findings position CSH-4044 as a promising lead for targeting PIM and DYRK families of kinases and highlight FWGE as a source of potential therapeutic compounds.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559357,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"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":0.9615,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1460569,"name":"Prabhadevi Venkataramani","orcid":"0000-0001-9106-0102","position":1,"is_corresponding":false},{"id":895258,"name":"Elad Elkayam","orcid":"0000-0001-9266-7002","position":2,"is_corresponding":false},{"id":442084,"name":"Keith Rivera","orcid":"0000-0003-2979-9576","position":3,"is_corresponding":false},{"id":1029431,"name":"Ankur Garg","orcid":"0000-0003-2397-1670","position":4,"is_corresponding":false},{"id":1460570,"name":"István Szabadkai","orcid":"0000-0002-8686-8382","position":5,"is_corresponding":false},{"id":1460571,"name":"László Őrfi","orcid":"0000-0001-6149-2385","position":6,"is_corresponding":false},{"id":335006,"name":"Leemor Joshua‐Tor","orcid":"0000-0001-8185-8049","position":7,"is_corresponding":false},{"id":442085,"name":"Darryl Pappin","orcid":"0000-0002-8981-8401","position":8,"is_corresponding":false},{"id":614542,"name":"Nicholas K. Tonks","orcid":"0000-0002-2394-1538","position":9,"is_corresponding":false},{"id":1461176,"name":"Gyula Bencze","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41279372","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":[]}