Identification and Validation of an Inhibitor of the Protein Kinases PIM and DYRK.

Fermented wheat germ extract (FWGE), a nutraceutical with reported anticancer properties, contains numerous biologically active molecules, but its therapeutic constituents remain unclear. In this study, we identify and characterize a novel small-molecule protein kinase inhibitor isolated from FWGE, designated F10V6W0. Through preparative high-performance liquid chromatography and structural elucidation via X-ray crystallography, this compound was revealed to be a unique benzothiazole. Kinase profiling demonstrated its selectivity toward PIM and DYRK protein kinase families. A chemically synthesized version (CSH-4044), mirrored the activity of the natural product, confirming structural integrity and biological equivalence. We determined the cocrystal structure of CSH-4044 bound to PIM1, revealing ATP-competitive binding and critical hydrophobic and hydrogen-bonding interactions. 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 kinase families and highlight FWGE as a potential therapeutic compounds.