Effects of geldanamycin and other naturally occurring small molecule antagonists of heat shock protein 90 on HER2 protein expression.
Several natural product antibiotics, including herbimycin, geldanamycin, and radicicol, bind to an amino terminal nucleotide binding pocket in the heat shock protein Hsp90. Drug binding alters the conformation of Hsp90 and interferes with its ability to chaperone a distinct group of "client" proteins, including a number of transmembrane and soluble tyrosine and serine/threonine kinases. Prominent among the kinases dependent on Hsp90 is the ErbB family member HER2, which is frequently overexpressed in adenocarcinoma and is associated with a poor prognosis and resistance to chemotherapy. Disruption of Hsp90 function promotes the proteasome-dependent and ubiquitin-mediated degradation of HER2, making small molecule chaperone antagonists exciting candidates for clinical development.
Neckers
L
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Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, Rockville, MD 20850, USA. len@helix.nih.gov