Heat shock protein 90 within epichaperome complexes (HSP90-epichaperome)

Heat shock protein 90 (HSP90) within epichaperome complexes represents a specialized, pathological conformation of the chaperone machinery where HSP90, HSP70, and various co-chaperones are organized into stable, high-molecular-weight networks (Rodina et al., 2016, Nature). In healthy cells, these chaperones typically exist in dynamic, transient states to facilitate protein folding and proteostasis (Joshi et al., 2018, Nature Communications). However, in diseased states such as cancer and neurodegeneration, these proteins form integrated epichaperome scaffolds that are essential for the survival of stressed cells by stabilizing aberrant oncoproteins or toxic protein aggregates (Inda et al., 2020, Nature Communications). This specific complex is a distinct therapeutic target because it exhibits a significantly higher affinity for certain small-molecule inhibitors compared to the individual chaperones in normal cells (Chiosis, 2021, Trends in Pharmacological Sciences). Drugs like PU-H71 selectively bind to the ATPase pocket of HSP90 when it is part of an epichaperome, leading to the collapse of the entire network and the degradation of its client proteins. This targeting strategy provides a therapeutic window to treat aggressive diseases while sparing healthy tissues that lack these stable complexes. Additionally, the presence of epichaperomes can be visualized and quantified using radiolabeled probes like [124I]-PU-H71, serving as a companion diagnostic for patient selection.

Other names

EpichaperomeHSP90-containing epichaperomeOncogenic chaperone networkPathological chaperone scaffoldHSP90-HSP70-co-chaperone complex

Selective inhibition of the ATPase activity of HSP90 when incorporated into stable, high-affinity epichaperome networks, leading to the destabilization and degradation of client proteins essential for disease progression.