Learning from Mistakes of the Past: Alternative Approaches towards Hsp90 Inhibition

The biological functions of life are heavily reliant upon the proteome. Consequently, cells have evolved several mechanisms through which proteostasis is maintained amid insults such as hypoxia and acidosis. Heat shock proteins represent a class of molecular chaperones expressed in response to elevated temperatures, and the 90-kiloDalton heat shock protein (Hsp90) is widely regarded as the “master regulator” of the heat shock response. Hsp90 is a ubiquitous ATPase that facilitates the maturation of >400 client protein substrates via an elaborate protein folding cycle. Because several of Hsp90’s clients are associated with the hallmarks of cancer upon mutation or overexpression, the pro-survival activities of Hsp90 can be exploited into promoting oncogenesis. Conversely, this also means that Hsp90 is a promising anticancer target, as its inhibition can manifest outcomes akin to combination therapy. Despite the selectivity of small-molecule, ATP-competitive Hsp90 inhibitors, the 22 compounds that have undergone clinical evaluation failed, or are expected to fail, due to unanticipated adverse toxicities. Hence, there is great demand for small molecules that bypass previous setbacks and achieve Hsp90 inhibition via alternative approaches. This dissertation discusses efforts that have been made towards these strategies. Chapter one presents an review of small molecules that have been identified to disrupt protein-protein interactions between Hsp90 and various co-chaperones and client substrates. Chapter two describes a structure-activity relationship (SAR) study of the macrocyclic natural product Enniatin A, which was recently reported to be an Hsp90 PPI disruptor with immunogenic activities. Chapter three recounts an SAR study on the indazolone ring system of KUNB106, an Hsp90ß-selective inhibitor designed to overcome the limitations of previous Hsp90 pan-inhibitors. Consequently, chapter four is a continuation of this work and features the development of KUNB106 “chimeras.” Lastly, chapter five details the preparation and characterization of fortilin inhibitors as a potential treatment for atherosclerosis.