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The Hsp90 family of molecular chaperones regulates and maintains cell homeostasis under proteotoxic stress and pathogenic pressure. In humans, Hsp90α and Hsp90β in the cytoplasm, Grp94 in the endoplasmic reticulum and Trap-1 in the mitochondria are the four Hsp90 paralogs. PU-WS13 is a potent, Grp94-specific Hsp90 inhibitor of the purine scaffold class.

In vitro: Brief treatment of SKBr3 cells with PU-WS13 disrupted the circular architecture of HER2 at the plasma membrane, resulting in a ‘shredded’ HER2 pattern. The effect of PU-WS13 on the HER2 surface architecture is mediated through Grp94. Upon treatment of cells with PU-WS13, a rapid accumulation of cells in the sub-G1 phase, PARP cleavage and a substantial increase in markers of early- and late-stage apoptosis were noted [1].

In vivo: Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with PUH71, a chemical analogue of PU-WS13. Notably, TNBC tumors respond to retreatment with PUH71 for several cycles extending for over 5 months without evidence of resistance or toxicity [2].

Clinical trial: Up to now, PU-WS13 is still in the preclinical development stage.

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