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Targeting multiple signal transduction pathways through inhibition of Hsp90

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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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Acknowledgements

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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  1. Department of Biology, Conforma Therapeutics Corporation, 9393 Towne Centre Dr., San Diego, CA, 92121, USA

    Hong Zhang & Francis Burrows

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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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