Abstract
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and / or survival. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2 / Neu (ErbB2), and HIF-1α. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and they have also shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, is currently in Phase I clinical trial. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Benzoquinone ansamycin binding to Hsp90 led to the identification of radicicol as an additional Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.
Keywords: molecular chaperones, heat shock protein 90, kinase inhibitors, benzoquinone ansamycins, radicicol, novobiocin, geldanamycin, molecularly targeted therapeutics
Current Medicinal Chemistry
Title: Development of Small Molecule Hsp90 Inhibitors: Utilizing Both Forward and Reverse Chemical Genomics for Drug Identification
Volume: 10 Issue: 9
Author(s): Len Neckers
Affiliation:
Keywords: molecular chaperones, heat shock protein 90, kinase inhibitors, benzoquinone ansamycins, radicicol, novobiocin, geldanamycin, molecularly targeted therapeutics
Abstract: Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and / or survival. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2 / Neu (ErbB2), and HIF-1α. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and they have also shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, is currently in Phase I clinical trial. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Benzoquinone ansamycin binding to Hsp90 led to the identification of radicicol as an additional Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.
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Cite this article as:
Neckers Len, Development of Small Molecule Hsp90 Inhibitors: Utilizing Both Forward and Reverse Chemical Genomics for Drug Identification, Current Medicinal Chemistry 2003; 10 (9) . https://dx.doi.org/10.2174/0929867033457818
DOI https://dx.doi.org/10.2174/0929867033457818 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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