3O2F

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

(2013) Nat Chem Biol 9: 677-684

• PubMed: 23995768 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/nchembio.1335
• Primary Citation of Related Structures:  
  3O0I, 3O2F


• PubMed Abstract: 
  

  Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90β, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers.

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Organizational Affiliation: 

1] Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York, USA. [2] Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA. [3].