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17-AAG

Targeting the Molecular Chaperone Heat Shock Protein 90

  • Chapter
Molecular Targeting in Oncology

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Summary

Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, and/or over-expressed signaling proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client proteins, and they have shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, has completed phase I clinical trials, and several phase II trials of this agent are planned or are in progress. Phase I testing of a related Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin, is currently in progress. Hsp90 inhibitors are unique in that, although they are directed toward a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. Furthermore, by inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective toward multiple forms of cancer.

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Authors
  1. Len Neckers PhD
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  2. Percy Ivy MD
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Editors and Affiliations

  1. Division of Surgical Oncology, Columbia University, New York, NY

    Howard L. Kaufman

  2. Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College Cornell University, New York, NY

    Scott Wadler

  3. Boston University Medical Campus Boston University School of Medicine, Boston, MA

    Karen Antman

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© 2008 Humana Press

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Neckers, L., Ivy, P. (2008). 17-AAG. In: Kaufman, H.L., Wadler, S., Antman, K. (eds) Molecular Targeting in Oncology. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-337-0_4

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  • DOI: https://doi.org/10.1007/978-1-59745-337-0_4

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