Abstract
The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of proteins, many of which are crucial in oncogenesis, including epidermal growth factor receptor (EGF-R), Her-2, AKT, Raf, p53, and cdk4. These proteins are referred to as “clients” of Hsp90. Under unstressed conditions these proteins form complexes with Hsp90 and the cochaperones to attain their active conformations or enhance stability. Inhibition of Hsp90 function disrupts the complex and leads to degradation of client proteins in a proteasome-dependent manner. This results in simultaneous interruption of many signal transduction pathways pivotal to tumor progression and survival. Based on the unique role of the Hsp90 complex, extensive effort has been made in identifying Hsp90 inhibitors. Several compounds have been shown to inhibit Hsp90 in vitro and in vivo and the most advanced, 17-allylamino-17-demethoxygeldanamycin (AAG), is in phase I/II clinical trials. Recent findings with 17-AAG indicate that tumor cells utilize Hsp90 quite differently from normal cells, explaining the selectivity of the drug and suggesting a central role of Hsp90 in malignant progression. Thus these small molecule inhibitors have proved not only to be of great value in identifying new Hsp90 client proteins and in understanding the biology of Hsp90 but are also promising therapeutics in a variety of tumors.
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Abbreviations
- 17-AAG :
-
17-Allylamino-17-demethoxygeldanamycin
- AML :
-
Acute myeloid leukemia
- CML :
-
Chronic myeloid leukemia
- EGF-R :
-
Epidermal growth factor receptor
- ERK :
-
Extracellular signal regulated kinase
- Flt :
-
FMS-like tyrosine kinase
- GM :
-
Geldanamycin
- Hsp :
-
Heat shock protein
- IKK :
-
IκB kinase
- JAK :
-
Janus kinase
- MAP :
-
Mitogen-activated protein
- MEK :
-
Mitogen-activated extracellular signal regulated kinase activating kinase
- NF :
-
Nuclear factor
- PDK :
-
Pyruvate dehydrogenase kinase
- PTEN :
-
Phosphatase and tensin homologue
- PI3K :
-
Phosphatidylinositol 3-kinase
- RD :
-
Radicicol
- STAT :
-
Signal transducer and activator of transcription
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We apologize to those authors whose work was not cited for reasons of space limitations. We thank our colleagues at Conforma Therapeutics for useful comments and suggestions.
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Zhang, H., Burrows, F. Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med 82, 488–499 (2004). https://doi.org/10.1007/s00109-004-0549-9
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DOI: https://doi.org/10.1007/s00109-004-0549-9