{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:01:49Z","timestamp":1785427309087,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,22]]},"group-title":"Biochemistry","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01CA53840"],"award-info":[{"award-number":["R01CA53840"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CA45508"],"award-info":[{"award-number":["CA45508"]}],"id":[{"id":"https:\/\/ror.org\/02qz8b764","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022504","name":"Hansen Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100022504","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02bxt4m23","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>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.<\/jats:p>","DOI":"10.1101\/2025.10.22.683941","type":"posted-content","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T03:35:14Z","timestamp":1761190514000},"source":"Crossref","is-referenced-by-count":1,"title":["Identification and Validation of an inhibitor of the protein kinases PIM and DYRK"],"prefix":"10.64898","author":[{"given":"Gyula","family":"Bencze","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhadevi","family":"Venkataramani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elad","family":"Elkayam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith D.","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankur","family":"Garg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Szabadkai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laszlo","family":"Orfi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leemor","family":"Joshua-Tor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl","family":"Pappin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas K.","family":"Tonks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102709450743000_2025.10.22.683941v2.1","doi-asserted-by":"publisher","DOI":"10.3390\/nu10101546"},{"key":"2025102709450743000_2025.10.22.683941v2.2","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2017.7604"},{"key":"2025102709450743000_2025.10.22.683941v2.3","doi-asserted-by":"publisher","DOI":"10.1186\/1756-9966-30-42"},{"key":"2025102709450743000_2025.10.22.683941v2.4","doi-asserted-by":"publisher","DOI":"10.1097\/IGC.0b013e318258509d"},{"key":"2025102709450743000_2025.10.22.683941v2.5","doi-asserted-by":"publisher","DOI":"10.1080\/01635581.2016.1153668"},{"key":"2025102709450743000_2025.10.22.683941v2.6","doi-asserted-by":"publisher","DOI":"10.1080\/01635580903285114"},{"issue":"4A","key":"2025102709450743000_2025.10.22.683941v2.7","first-page":"2353","article-title":"Effect of Avemar and Avemar + Vitamin C on Tumor Growth and Metastasis in Experimental Animals","volume":"18","year":"1998","journal-title":"Anticancer Res"},{"key":"2025102709450743000_2025.10.22.683941v2.8","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2986"},{"key":"2025102709450743000_2025.10.22.683941v2.9","doi-asserted-by":"publisher","DOI":"10.4161\/23723548.2014.970048"},{"key":"2025102709450743000_2025.10.22.683941v2.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-71118-3"},{"key":"2025102709450743000_2025.10.22.683941v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2005.02.039"},{"key":"2025102709450743000_2025.10.22.683941v2.12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M413155200"},{"key":"2025102709450743000_2025.10.22.683941v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.06.050"},{"key":"2025102709450743000_2025.10.22.683941v2.14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307933200"},{"key":"2025102709450743000_2025.10.22.683941v2.15","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-4272"},{"key":"2025102709450743000_2025.10.22.683941v2.16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2007.00390.x"},{"key":"2025102709450743000_2025.10.22.683941v2.17","doi-asserted-by":"publisher","DOI":"10.3892\/or.2014.3158"},{"key":"2025102709450743000_2025.10.22.683941v2.18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707358200"},{"key":"2025102709450743000_2025.10.22.683941v2.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-00682-y"},{"key":"2025102709450743000_2025.10.22.683941v2.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2019.134541"},{"issue":"3","key":"2025102709450743000_2025.10.22.683941v2.21","first-page":"563","article-title":"Fermented Wheat Germ Extract Induces Apoptosis and Downregulation of Major Histocompatibility Complex Class I Proteins in Tumor T and B Cell Lines","volume":"20","year":"2002","journal-title":"Int. J. Oncol"},{"key":"2025102709450743000_2025.10.22.683941v2.22","doi-asserted-by":"publisher","DOI":"10.1089\/cbr.2004.19.746"},{"key":"2025102709450743000_2025.10.22.683941v2.23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206150200"},{"key":"2025102709450743000_2025.10.22.683941v2.24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510711200"},{"key":"2025102709450743000_2025.10.22.683941v2.25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409123200"},{"key":"2025102709450743000_2025.10.22.683941v2.26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007112"},{"key":"2025102709450743000_2025.10.22.683941v2.27","doi-asserted-by":"publisher","DOI":"10.1107\/S0108768104031738"},{"key":"2025102709450743000_2025.10.22.683941v2.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiomed.2020.103641"},{"key":"2025102709450743000_2025.10.22.683941v2.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13557-z"},{"key":"2025102709450743000_2025.10.22.683941v2.30","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006098"},{"key":"2025102709450743000_2025.10.22.683941v2.31","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0804-2"},{"key":"2025102709450743000_2025.10.22.683941v2.32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M404440200"},{"issue":"3","key":"2025102709450743000_2025.10.22.683941v2.33","first-page":"258","article-title":"Pim-1 Phosphorylates the DNA Binding Domain of c-Myb","volume":"2","year":"2003","journal-title":"Cell Cycle Georget. Tex"},{"key":"2025102709450743000_2025.10.22.683941v2.34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.4.1524"},{"key":"2025102709450743000_2025.10.22.683941v2.35","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.10"},{"key":"2025102709450743000_2025.10.22.683941v2.36","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1105003"},{"key":"2025102709450743000_2025.10.22.683941v2.37","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(00)01105-4"},{"key":"2025102709450743000_2025.10.22.683941v2.38","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80141-0"},{"key":"2025102709450743000_2025.10.22.683941v2.39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.26.18659"},{"key":"2025102709450743000_2025.10.22.683941v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/s0167-4889(02)00347-6"},{"key":"2025102709450743000_2025.10.22.683941v2.41","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2011.01966.x"},{"key":"2025102709450743000_2025.10.22.683941v2.42","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.24343"},{"key":"2025102709450743000_2025.10.22.683941v2.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2015.03.004"},{"key":"2025102709450743000_2025.10.22.683941v2.44","doi-asserted-by":"publisher","DOI":"10.2174\/18715273113126660186"},{"key":"2025102709450743000_2025.10.22.683941v2.45","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22169098"},{"key":"2025102709450743000_2025.10.22.683941v2.46","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-165837"},{"key":"2025102709450743000_2025.10.22.683941v2.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.03.050"},{"key":"2025102709450743000_2025.10.22.683941v2.48","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.149"},{"key":"2025102709450743000_2025.10.22.683941v2.49","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444911007773"},{"key":"2025102709450743000_2025.10.22.683941v2.50","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889807021206"},{"key":"2025102709450743000_2025.10.22.683941v2.51","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"2025102709450743000_2025.10.22.683941v2.52","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909052925"},{"key":"2025102709450743000_2025.10.22.683941v2.53","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909042073"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.22.683941","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:13:13Z","timestamp":1782277993000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.22.683941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":53,"URL":"https:\/\/doi.org\/10.1101\/2025.10.22.683941","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1021\/acs.jmedchem.5c03226","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,10,22]]},"subtype":"preprint"}}