Therapeutic and diagnostic implications of Hsp90 activation.
The molecular chaperone heat-shock protein 90 (Hsp90) is involved in the stabilization and conformational maturation of many signaling proteins that are deregulated in cancers. Hsp90 inhibition results in the proteasomal degradation of these client proteins and leads to potent antitumor activity. The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is presently in clinical trials. Recent work has identified the role of Hsp90 in multiple signal transduction pathways and revealed that the molecular mechanism of tumor selectivity by Hsp90 inhibitors is the result of an activated, high-affinity conformation of Hsp90 in tumors. This review discusses these recent advances in the understanding of tumor Hsp90 for the treatment and diagnosis of cancer. In addition, the role of Hsp90 in non-oncological diseases will also be discussed.
Kamal
Adeela
A
Department of Biology, Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, CA 92121, USA. akamal@conformacorp.com
Boehm
Marcus F
MF
Burrows
Francis J
FJ
D000818:Animals; D016227:Benzoquinones; D002986:Clinical Trials as Topic; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin; D046988:Proteasome Endopeptidase Complex