Targeting Hsp90 for the treatment of cancer.
Heat shock protein (Hsp)90 is a molecular chaperone that is responsible for the correct folding of a large number of proteins, which allows these proteins to achieve their functional conformation. Client proteins of Hsp90 include many overexpressed or mutated oncogenes that are known to be critical for the transformed phenotype observed in tumors. The compounds 17-AAG (Kosan Biosciences Inc/National Cancer Institute) and 17-DMAG (Kosan Biosciences Inc/National Cancer Institute) are Hsp90 inhibitors that are derived from the prototypical ansamycin natural product Hsp90 inhibitor geldanamycin. These compounds have demonstrated preclinical efficacy in mouse xenograft models, and are now undergoing phase II and I clinical trials, respectively. Preclinical efficacy studies of these compounds are collated and discussed in this review. More recent disclosures of small-molecule Hsp90 inhibitors include purine and resorcinol analogs, and the first small-molecule Hsp90 compounds showing oral efficacy have been described. Inhibition of Hsp90 not only results in the degradation of client proteins, but also results in the induction of another chaperone, Hsp70. Hsp70 is known to be anti-apoptotic, and therefore the induction of Hsp70 may ultimately limit the efficacy of Hsp90 inhibitors under certain circumstances. Histone deacetylase inhibitors have recently been demonstrated to exert some of their effect through modulation of Hsp90 chaperoning activity, and some mechanistic aspects of this control are also discussed herein.
Drysdale
Martin J
MJ
Vernalis Ltd, Granta Park, Great Abington, Cambridge, CB1 6GB, UK. m.drysdale@vernalis.com
Brough
Paul A
PA
Massey
Andrew
A
Jensen
Michael Rugaard
MR
Schoepfer
Joseph
J
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins