Reinventing Hsp90 Inhibitors: Blocking C‐Terminal Binding Events to Hsp90 by Using Dimerized Inhibitors

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone (90 kDa) that functions as a dimer. This protein facilitates the folding, assembly, and stabilization of more than 400 proteins that are responsible for cancer development and progression. Inhibiting Hsp90's function will shut down multiple cancer-driven pathways simultaneously because oncogenic clients rely heavily on Hsp90, which makes this chaperone a promising anticancer target. Classical inhibitors that block the binding of adenine triphosphate (ATP) to the N-terminus of Hsp90 are highly toxic to cells and trigger a resistance mechanism within cells. This resistance mechanism comprises a large increase in prosurvival proteins, namely, heat shock protein 70 (Hsp70), heat shock protein 27 (Hsp27), and heat shock factor 1 (HSF-1). Molecules that modulate the C-terminus of Hsp90 are effective at inducing cancer-cell death without activating the resistance mechanism. Herein, we describe the design, synthesis, and biological binding affinity for a series of dimerized C-terminal Hsp90 modulators. We show that dimers of these C-terminal modulators synergistically inhibit Hsp90 relative to monomers.

Hsp90 in Human Diseases: Molecular Mechanisms to Therapeutic Approaches

“…An alternate driving force is the strategy to lessen this heat shock response by use of the C-terminal domain (CTD) targeting Hsp90 inhibitors. This class of inhibitors fall into two categories: inhibitors that directly target the C-terminus and inhibitors that disrupt the binding of Hsp90 to co-chaperons that bind to the CTD of Hsp90 [137]. Like the NTD, the CTD also contains the ATP binding site but lacks ATPase activity [8].…”

A Chemical Biology Approach to the Chaperome in Cancer—HSP90 and Beyond

“…Soon after, the toolbox of HSP90 probes started to fill, first with radicicol (Schulte et al 1998) and other natural products (Amolins and Blagg 2009), followed by synthetic probes, such as PU3 (Chiosis et al 2001), a ligand designed to interact with the regulatory pocket of HSP90. Other interactors soon followed: first came probes that bound to the ATP-binding pocket (Messaoudi et al 2011;Patel et al 2011;Jhaveri et al 2014;Taldone et al 2014b), but today the HSP90 toolbox has expanded to include allosteric regulators that bind in noncanonical ways, including those that target the carboxy-terminal domain of HSP90 (Koay et al 2016;Kumar et al 2018;Ferraro et al 2019) and those that target protein-protein interactions between HSP90 and cochaperones (Yang et al 2006;Cortajarena et al 2008;Yi and Regan 2008;Zhang et al 2008;Sreeramulu et al 2009;Yi et al 2009) or client proteins (Plescia et al 2005;Meli et al 2006;Liu et al 2010). Following this and a deeper understanding of ligand-binding modes was a chemical toolset to selectively probe HSP90 paralogs in humans (Altieri et al 2012;Patel et al 2013;Gewirth 2016;Shrestha et al 2016b;Que et al 2018) and HSP90 in other organisms (Wang et al 2014).…”

Hsp90 Mediates Membrane Deformation and Exosome Release

“…ATP-dependent manner (Hessling et al, 2009) (Figure 2A). To assess if Hsp90 conformation affects membrane deformation, we used different Hsp90 inhibitors that preferentially bind to the dimer in the open (the geldanamycin-analog 17-allylamino-17-demethoxygeldanamycin [Johnson et al, 2010;Schulte and Neckers, 1998]) or the closed state (the sansalvamide A derivatives SM122 and SM253 [Alexander et al, 2011;Koay et al, 2016]). All three compounds reduce b-galactosidase activity in the chaperone assay to background levels, indicating they are active in vivo (Figures 2A and 2B).…”