Гелданамицин

Geldanamycin from Streptomyces hygroscopicus.
Geldanamycin is a benzoquinone ansamycin antitumor antibiotic. Geldanamycin binds specifically to Hsp90 (Heat Shock Protein 90) and to its endoplasmic reticulum homologue GP96. The Hsp90 chaperone is required for the activation of several families of eukaryotic protein kinases and nuclear hormone receptors, many of which are proto-oncogenic and play a prominent role in cancer. The geldanamycin antibiotic has antiproliferative and antitumor effects, as it binds to Hsp90, inhibits the Hsp90-mediated conformational maturation/refolding reaction, and results in the degradation of Hsp90 substrates. Hsp90 also plays a key role in regulating the physiology of cells exposed to environmental stress and thus, geldanamycin interferes with cellular stress response.
Geldanamycin was found to be a potent antibiotic active at nanomolar concentrations against 60 cell lines as well as in mouse tumor models.
It is an inhibitor of proto-oncogenic protein kinases, such as erbB22, EFG receptor tyrosine kinases, and non-receptor tyrosine kinases, such as v-src and Raf-1. In addition, it is a potent inhibitor of the nuclear hormone receptor family including the estrogen and androgen hormone receptors.

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Geldanamycin is a potent antitumor antibiotic active at nanomolar concentration against 60 cell lines. It binds specifically to the heat shock protein Hsp90 and to its endoplasmic reticulum homologue GP96, and thus interferes with conformational maturation of proteins and the cellular stress response. In addition, it is a potent inhibitor of the nuclear hormone receptor family.

ChEBI: An ansamycin consisting of a 19-membered macrocyle incorporating a benzoquinone ring and a lactam functionality. It shows antimicrobial activity against many Gram-positive and some Gram-negative bacteria.

Chemical structure: benzenoid

Selectively inhibits heat shock protein 90 (Hsp90). Binds to the ATP site of Hsp90 (K d = 1.2 μ M) and inhibits its chaperone activity. Consequently inhibits activities of oncogenic kinases (e.g. src, Raf), p53 and steroid receptors.