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<a href="http://www.fermentek.co.il/geldanamycin.htm">Pure geldanamycin is produced by Fermentek in batches 12 kg large</a>
The benzoquinone ansamycin
17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares
important biologic activities with geldanamycin.
Schulte TW,
Neckers LM.
Medicine Branch, National Cancer Institute, National Institutes
of Health, Bethesda, MD 20892-1928, USA. tschulte@helix.nih.gov
PURPOSE: Benzoquinone ansamycins are antibiotics with anticancer
potential. First described as tyrosine kinase inhibitors, they are
now frequently used to target HSP90 chaperone function. While
herbimycin A and geldanamycin have been widely used in
preclinical studies, both drugs are poor candidates for clinical
trials owing to their in vivo toxicity and lack of stability. We
therefore examined the biologic effects of
17-allylamino-17-demethoxygeldanamycin (17AAG), an ansamycin
derivative with lower in vivo toxicity than geldanamycin. METHODS:
Binding of 17AAG to HSP90 was studied in vitro using a geldanamycin-affinity
beads competition assay. We analyzed the drug-induced
destabilization of p185erbB2, Raf-1 and mutant p53 in SKBR3 breast
cancer cells by Western blotting. The antiproliferative activities
of 17AAG and geldanamycin were compared using the MTT assay.
RESULTS: We found that, in a similar manner to geldanamycin itself,
17AAG bound specifically to HSP90. It also led to degradation of the
receptor tyrosine kinase p185erbB2, the serine/threonine kinase
Raf-1 and mutant p53. Both geldanamycin and 17AAG displayed
comparable antiproliferative effects in SKBR3 and MCF7 cells. Even
though HSP90 binding by 17AAG was weaker than by geldanamycin, 17AAG
and geldanamycin caused biologic effects in tumor cells at similar
doses. CONCLUSION: 17AAG shares the important biologic features of
its parent compound geldanamycin. Since 17AAG has a better toxicity
profile than geldanamycin, it is an interesting candidate
benzoquinone ansamycin for clinical development.
