Natural product inspired HSP90 inhibitors

Natural products continue to play a key role in drug discovery, an example of which is highlighted by Hsp90 inhibitors. The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides, many of which are critical to the maintenance of cell signaling networks that contribute to the six hallmarks of cancer. Thus, through Hsp90 inhibition, one can simultaneously derail multiple signaling networks through inhibition of a single biological target. The natural products, geldanamycin and radicicol, have served as lead compounds to develop multiple inhibitors that have entered clinical trials for the treatment of cancer that manifest their activity through inhibition of the Hsp90 N-terminal ATPase domain. In contrast, the natural products, novobiocin, EGCG, and silybin have served as lead compounds that regulate Hsp90 protein folding activity through allosteric modulation of the chaperone via the C-terminal dimerization domain. In addition, the natural products, cruentaren A, celastrol and gedunin, have shown to provide a unique opportunity to modulate Hsp90 activity through disruption of co-chaperone interactions with Hsp90. In this presentation, the utilization of natural products to modulate the Hsp90 protein folding machinery will be discussed along with their potential therapeutic applications.