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

Nat Chem Biol. 2013 Nov;9(11):677-84. doi: 10.1038/nchembio.1335. Epub 2013 Sep 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / chemistry
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Purines / chemical synthesis
  • Purines / chemistry
  • Purines / pharmacology*
  • Receptor, ErbB-2 / metabolism*
  • Structure-Activity Relationship

Substances

  • HSP90 Heat-Shock Proteins
  • Purines
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • purine

Associated data

  • PDB/3O0I
  • PDB/3O2F
  • PubChem-Substance/163826355
  • PubChem-Substance/163826356
  • PubChem-Substance/163826357
  • PubChem-Substance/163826358
  • PubChem-Substance/163826359
  • PubChem-Substance/163826360
  • PubChem-Substance/163826361
  • PubChem-Substance/163826362
  • PubChem-Substance/163826363
  • PubChem-Substance/163826364
  • PubChem-Substance/163826365
  • PubChem-Substance/163826366
  • PubChem-Substance/163826367
  • PubChem-Substance/163826368
  • PubChem-Substance/163826369
  • PubChem-Substance/163826370
  • PubChem-Substance/163826371
  • PubChem-Substance/163826372
  • PubChem-Substance/163826373
  • PubChem-Substance/163826374
  • PubChem-Substance/163826375
  • PubChem-Substance/163826376