A New Generation of Hsp90 Inhibitors: Addressing Isoform Selectivity and Heat Shock Induction

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that are upregulated in response to cellular stress and are responsible for the conformational maturation, activation and/or stability of more than 200 client proteins. Many of these clients are oncogenic and facilitate the progression of cancer. Disruption of Hsp90's inherent ATPase activity renders the chaperone inactive, leading to degradation of substrates and ultimately, apoptosis. Consequently, Hsp90 has become a highly sought after anti-cancer target and numerous pharmaceutical companies and academic labs are expending efforts to develop novel methods to regulate the Hsp90-mediated protein folding process. Included within the Hsp90 family are four isoforms, each of which exhibits a unique cellular localization, expression, function and clientele. Hsp90α (inducible) and Hsp90β (constitutive) both localize to the cytoplasm and share similar functions; however, recent studies have identified isoform specific substrates. Tumor necrosis factor receptor-associated protein (TRAP-1) is the Hsp90 isoform localized to the mitchondria and to date, no specific clients or selective inhibitors have been identified. The fourth isoform is glucose-regulated protein 94 kDa (Grp94), which is localized to the endoplasmic reticulum and is responsible for the maturation and stability of specific secreted and membrane bound proteins. Currently identified Hsp90 inhibitors exhibit pan-inhibition, resulting in the disruption of all four isoforms' ability to bind and hydrolyze ATP. This activity is believed responsible for the undesired toxicities related to Hsp90 inhibition in the clinic, as proteins that are critical to cardio function and the central nervous system are dependent upon yet to be determined Hsp90 isoforms. Another detriment arising from N-terminal Hsp90 inhibition is induction of the pro-survival, heat shock response. Specifically, induction of the target, Hsp90, has resulted in therapeutic resistance and complications with dosing and administration protocols. Presented herein is rationale for the development of Hsp90 isoform selective inhibitors and the first irreversible inhibitor of Hsp90 that mitigates induction of Hsp90; thus, providing key advancements towards addressing the detriments associated with Hsp90 inhibitors currently under clinical investigation