Identification and characterization of natural compound inhibitors of the Hsp90 chaperone complex

Abstract

The 90 kDa Heat Shock Protein (Hsp90) has emerged as a major therapeutic target for a number of diseases, the most notable of which is cancer. Accordingly, many groups are attempting to develop small molecules that modulate the activity of this chaperone and its associated co-chaperones. At the same time, many of these same diseases have traditionally been treated using substances derived from local plant species. Recognizing the intersection between these two medicinal strategies, our group has sought to find novel inhibitory compounds against the Hsp90 chaperone machine by employing high through put screens of natural compound libraries. In this work, we report the results off our such screens, showing that a number of potential Hsp90 inhibitors have already been used successfully in various medical traditions for the treatment of multiple diseases. Characterization of structure-activity relationships using a 1,4- nathoquinone scaffold that was common to several of our natural product hits, demonstrated that the luciferase renaturation assay that forms the basis of our screens is comparable to cell-based assays. Four compound hits, anthothecol, garcinol, rottlerin, and piperlongumine, were further characterized and demonstrated to inhibit the proliferation of human cancer cells, and the maturation of an Hsp90-dependent kinase. Additionally, one of the compounds, gambogic acid, was shown to disrupt inter-molecular interactions of the Hsp90 chaperone complex, and to interact with Hsp90 itself. These compounds and their derivatives represent potential novel therapeutics against cancer and other diseases in which Hsp90 plays a role.