Repositioning Irsogladine to Hsp90 Inhibitor

|Heat shock protein 90 (Hsp90) is a ubiquitous adenosine triphosphate (ATP)-dependent molecular chaperone and represents an attractive cancer therapeutic target due to its role in maintaining the correct folding and stability of many oncogenic proteins. In our effort to repurpose existing drugs to Hsp90 inhibitors, we screened Food and Drug Administration (FDA) approved drugs based on chemical structure similarity and discovered that a mucosal protective drug, irsogladine, inhibits the Hsp90 folding machinery. In vitro fluorescence polarization assay and cell-based mechanism study demonstrate that irsogladine binds to the ATP-binding pocket in N-terminal domain of Hsp90 and impairs the Hsp90 chaperoning function. Consequently, irsogladine induces the downregulation of Hsp90 client proteins including Her2, Akt, and Cdk4 and upregulation of the co-chapereone Hsp70.