ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system

Nat Chem Biol. 2013 May;9(5):307-12. doi: 10.1038/nchembio.1212. Epub 2013 Mar 17.


Protein kinase clients are recruited to the Hsp90 molecular chaperone system via Cdc37, which simultaneously binds Hsp90 and kinases and regulates the Hsp90 chaperone cycle. Pharmacological inhibition of Hsp90 in vivo results in degradation of kinase clients, with a therapeutic effect in dependent tumors. We show here that Cdc37 directly antagonizes ATP binding to client kinases, suggesting a role for the Hsp90-Cdc37 complex in controlling kinase activity. Unexpectedly, we find that Cdc37 binding to protein kinases is itself antagonized by ATP-competitive kinase inhibitors, including vemurafenib and lapatinib. In cancer cells, these inhibitors deprive oncogenic kinases such as B-Raf and ErbB2 of access to the Hsp90-Cdc37 complex, leading to their degradation. Our results suggest that at least part of the efficacy of ATP-competitive inhibitors of Hsp90-dependent kinases in tumor cells may be due to targeted chaperone deprivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / antagonists & inhibitors*
  • Binding, Competitive
  • Cell Cycle Proteins / metabolism*
  • Chaperonins / metabolism*
  • HSP90 Heat-Shock Proteins / metabolism*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Lapatinib
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Vemurafenib


  • CDC37 protein, human
  • Cell Cycle Proteins
  • HSP90 Heat-Shock Proteins
  • Indoles
  • Protein Kinase Inhibitors
  • Quinazolines
  • Sulfonamides
  • Lapatinib
  • Vemurafenib
  • Adenosine Triphosphate
  • Protein Kinases
  • Chaperonins