Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2

Area of Science:

• Molecular Biology
• Cancer Research
• Chemical Biology

Background:

• The Heat Shock Protein 90 (Hsp90) chaperone family, comprising Hsp90α, Hsp90β, Grp94, and Trap-1 in humans, plays a critical role in malignancy.
• Understanding the specific contribution of each Hsp90 paralog to cancer phenotypes has been limited by the lack of paralog-specific reagents.
• This knowledge gap hinders the development of targeted cancer therapies.

Purpose of the Study:

• To identify and characterize novel purine-based chemical tools with specificity for individual Hsp90 paralogs.
• To utilize these chemical tools to investigate the distinct roles of Hsp90 paralogs in cancer cell regulation.
• To elucidate the mechanistic basis for the efficacy of selective Grp94 inhibition in specific breast cancers.

Main Methods:

• Screening of a compound library to identify Hsp90 paralog-specific inhibitors.
• Structural and computational analyses to determine the binding modes and selectivity determinants of identified compounds.
• Application of newly developed chemical tools to study Hsp90 paralog function in cancer cells.

Main Results:

• Identification of purine-based chemical tools exhibiting specificity for Hsp90 paralogs.
• Discovery of a novel allosteric pocket in Grp94 responsible for the selectivity of certain compounds.
• Demonstration that cancer cells utilize individual Hsp90 paralogs for tumor-specific client protein regulation.
• Evidence linking proteome alterations to the differential usage of Hsp90 paralogs.

Conclusions:

• Development of specific chemical probes enables the dissection of individual Hsp90 paralog functions in cancer.
• Selective inhibition of Grp94 shows particular efficacy in certain breast cancers, supported by new mechanistic insights.
• These findings pave the way for developing targeted therapies based on Hsp90 paralog-specific inhibition.