Affiliations: Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, Rockville, MD 20850, USA
Correspondence:
[*]
Correspondence to: Len Neckers, Ph.D., Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, USA. Tel.: +1 301 402 3128, x318; Fax: +1 301 402 4422; E-mail: [email protected]
Abstract: 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.
DOI: 10.3233/BD-1999-11105
Journal: Breast Disease, vol. 11, no. 1, pp. 49-59, 1999
