Hsp90 Inhibitors as Novel Cancer Chemotherapeutic Agents

Trends Mol Med. 2002;8(4 Suppl):S55-61. doi: 10.1016/s1471-4914(02)02316-x.

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and over-expressed signaling proteins that promote the growth and/or survival of cancer cells. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, ErbB2 and hypoxia-inducible factor 1 alpha (HIF-1 alpha). Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and they have shown promising antitumor activity in preclinical model systems. One Hsp90 inhibitor, 17-allylaminogeldanamycin (17AAG), is currently in phase I clinical trial. Because of the chemoprotective activity of several proteins that are Hsp90 clients, the combination of an Hsp90 inhibitor with a standard chemotherapeutic agent could dramatically increase the in vivo efficacy of the therapeutic agent.

Publication types

  • Review

MeSH terms

  • Antibiotics, Antineoplastic / therapeutic use*
  • Benzoquinones
  • Clinical Trials as Topic
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Lactams, Macrocyclic
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Quinones / therapeutic use
  • Transcription Factors / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Quinones
  • Transcription Factors
  • Protein-Tyrosine Kinases
  • geldanamycin