The Pursuit of Unshocking Hsp90 Inhibitors: Development of Gedunin and Cruentaren A as Chemical Leads

Abstract: The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that is critical cellular survival and growth under both typical and stressful conditions. Hsp90 is responsible for the maturation and stability of more than 200 client proteins involved in a diverse assortment of cellular processes. Disruption of Hsp90's chaperoning activity causes client protein degradation and ultimately leads to cytostasis and/or apoptosis. While this phenomenon is observed in normal cells, the effects of Hsp90 inhibition are more pronounced in oncogenic cell lines as a result of higher expression levels and increased cellular dependence on Hsp90 activity. As such, targeting Hsp90 inhibition with small molecules has emerged as a powerful strategy for the development of anticancer chemotherapeutics.;Several small molecule Hsp90 inhibitors are currently under evaluation in FDA sanctioned clinical trials for the treatment of various cancers, however, some undesired side effects have been observed. All of the Hsp90 targeting small molecules involved in these trials are ATP competitive inhibitors that bind at the N-terminal ATP binding domain. Inhibitors of this class elicit non-specific client protein degradation and cause the induction of the heat shock response that results in an upregulation of Hsp90 and other Hsp expression levels following incubation within cells. As a result, untoward toxicological effects are observed and the determination of appropriate dosing schedules to mitigate the heat shock response is highly complicated. A new strategy for Hsp90 inhibition capable of targeting specific client proteins for therapeutic efficacy that avoids heat shock response induction is desired.;Presented herein are preliminary studies that investigate potential strategies to target the selective degradation of Hsp90 client proteins while avoiding the heat shock response. Specifically, small molecule natural products that elicit Hsp90 co-chaperone disruption are considered and the chemical and biological results are discussed. These studies provide the first steps toward developing a second generation of Hsp90 inhibitors that circumvent the detrimental effects observed for clinically evaluated inhibitors.