Penicisulfuranol A, a novel C-terminal inhibitor disrupting molecular chaperone function of Hsp90 independent of ATP binding domain.

The goal of this study is to explore the mechanism of a heat shock protein 90 (Hsp90) C-terminal inhibitor, Penicisulfuranol A (PEN-A), for cancer therapy. PEN-A was produced by a mangrove endophytic fungus Penicillium janthinellum and had a new structure with a rare 3H-spiro [benzofuran-2, 2'-piperazine] ring system. PEN-A caused depletion of multiple Hsp90 client proteins without induction of heat shock protein 70 (Hsp70). Subsequently, it induced apoptosis and inhibited xerograph tumor growth of HCT116 cells in vitro and in vivo. Mechanism studies showed that PEN-A was bound to C-terminus of Hsp90 at the binding site different from ATP binding domain. Therefore, it inhibited dimerization of Hsp90 C-terminus, depolymerization of ADH protein by C-terminus of Hsp90, and interaction of co-chaperones with Hsp90. These inhibitory effects of PEN-A were similar to those of novobiocin, an inhibitor binding to interaction site for ATP of C-terminus of Hsp90. Furthermore, our study revealed that disulfide bond was essential moiety for inhibition activity of PEN-A on Hsp90. This suggested that PEN-A may be bound to cysteine residues near amino acid region which was responsible for dimerization of Hsp90. All results indicate that PEN-A is a novel C-terminal inhibitor of Hsp90 and worthy for further study in the future not only for drug development but also for unraveling the bioactivities of Hsp90.