Heat shock protein 90 N-terminal ATP-binding site within epichaperome complexes (HSP90-EPI)

The Heat shock protein 90 (HSP90) N-terminal ATP-binding site within epichaperome complexes is a specialized therapeutic target found in cells where the proteostasis network has been pathologically rewired (Rodina et al., 2016, Nature). In healthy cells, HSP90 functions in transient, dynamic cycles; however, in many cancers and neurodegenerative diseases, it forms stable, high-molecular-weight complexes known as epichaperomes that are essential for the survival of the diseased cell (Inda et al., 2020, Nature Communications). These complexes act as scaffolds that stabilize a wide array of oncogenic or toxic proteins, making the cell addicted to the epichaperome. Drugs like PU-H71 target the N-terminal ATP-binding pocket specifically when HSP90 is in this complexed state, leading to the collapse of the network and the degradation of its client proteins (Pillarsetty et al., 2012, J Med Chem). This target is particularly valuable because it allows for a wider therapeutic window than pan-HSP90 inhibition, as the epichaperome is largely absent in normal tissues. Clinical strategies often involve using radiolabeled inhibitors as PET imaging biomarkers to select patients whose tumors are driven by these complexes (Dunphy et al., 2020, Cancer Cell). Despite the promise, challenges remain, including managing the ocular and systemic toxicities historically associated with the HSP90 inhibitor class.

Other names

EpichaperomeHSP90-containing epichaperomeHigh-affinity HSP90 complexOncogenic chaperone networkHSP90-HSP70-co-chaperone complex

Competitive inhibition of the N-terminal ATP-binding pocket of HSP90 within the epichaperome complex, leading to complex disassembly and proteasomal degradation of client proteins.