Bencze, Gyula, Venkataramani, Prabhadevi, Elkayam, Elad, Rivera, Keith D, Garg, Ankur, Szabadkai, Istvan, Orfi, Laszlo, Joshua-Tor, Leemor, Pappin, Darryl, Tonks, Nicholas K (October 2025) Identification and Validation of an inhibitor of the protein kinases PIM and DYRK. bioRxiv. ISSN 2692-8205 (Submitted)
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.
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