Geldanamycin (GA), a benzoquinone ansamycin antibiotic, interferes with the action of the heat shock protein 90 (Hsp90) leading to the degradation of Hsp90 client proteins. Since many of these client proteins are oncogenic proteins, GA inhibits the proliferation of cancer cells and shows anticancer activity in experimental animals.
However due to poor aqueous solubility and liver toxicity, GA has not moved forward in clinical trials. To overcome these undesirable properties, numerous GA analogues have been synthesized which differ only in their 17-substituent. These include 17-allylamino-demethoxygeldamycin (17-AAG) and 17-dimethylamino- geldanamycin (17-DMAG) that have completed phase I and are currently entering phase II clinical trials.
InvivoGen provides Geldanamycin and four of its more promising analogues as well as other derivatives. Bulk quantity readily available - contact us
Geldanamycin
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Description
Geldanamycin (GA) is a natural product produced by Streptomyces hygroscopicus. InvivoGen produces GA from a mutant strain of S. hygroscopicus, inactivated for the synthesis of nigericin, a common contaminant of GA. GA binds with high affinity into the ATP binding pocket of Hsp90. Hsp90 is a ubiquitous molecular chaperone critical for the folding, assembly and activity of multiple mutated and overexpressed signaling proteins that promote the growth and/or survival of tumor cells. Hsp90 client proteins include mutated p53, Raf-1, Akt, ErbB2 and hypoxia-inducible factor 1α (HIF-1α)[1]. Binding of GA to Hsp90 causes the destabilization and degradation of its client proteins[2].
1. Neckers L., 2002. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 8(4 Suppl):S55-61 2. Whitesell L. et al., 1994. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A 91(18):8324-8
Formula
Formula: C29H40N2O9 Molecular weight: 560.64 CAS Number : 30562-34-6
Contents and Storage
Geldanamycin is provided as a yellow powder. Geldanamycin is shipped at room temperature. Store at -20°C in the dark. Geldanamycin is stable for 6 months when stored properly.
17-Allylamino-17-demethoxygeldanamycin (17-AAG) is an analogue chemically derived from GA. 17-AAG is a less toxic and more stable analogue of geldanamycin (GA)[1]. Even though 17-AAG binding to Hsp90 is weaker than GA, 17-AAG displays similar antitumor effects as GA and a better toxicity profile. 17-AAG is currently in phase I clinical trial in several centers worldwide. Preliminary data obtained from these trials demonstrate that antitumor activity is achieved at concentrations below the maximum tolerated dose[2].
1. Schulte TW. & Neckers LM., 1998. The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 42(4):273-9 2. Agnew EB. et al. 2001. Measurement of the novel antitumor agent 17-(allylamino)-17-demethoxygeldanamycin in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 755:237-43
Formula
Formula: C31H43N3O8 Molecular weight: 585.69 CAS Number : 75747-14-7
Contents and Storage
17-AAG is provided as a purple powder. 17AAG is shipped at room temperature. Store at -20°C in the dark. 17-AAG is stable for 6 months when stored properly.
Description 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG, NSC 707545) is the first water-soluble analogue of 17-AAG. This Hsp90 inhibitor shows promise in preclinical models[1]. 17-DMAG has excellent bioavailability, is widely distributed to tissues, and is quantitatively metabolized much less than is 17-AAG[2].
1. Workman P., 2003. Overview: translating Hsp90 biology into Hsp90 drugs. Curr Cancer Drug Targets 3(5):297-300 2. Egorin MJ, et al., 2002. Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)- 17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol 49(1):7-19
Formula
Formula: C32H48N4O8, HCl Molecular weight: 652
Contents and Storage
17-DMAG is provided as a purple powder. 17-DMAG is shipped at room temperature. Store at -20°C in the dark. 17-DMAG is stable for 6 months when stored properly.
The use of 17-DMAG is covered under US Patent 6,890,917 owned and licensed by the NIH to InvivoGen.
17-[2-(Pyrrolidin-1-yl)ethyl]aminno-17-demethoxygeldanamycin (17-AEP-GA) is a new geldanamycin (GA) analogue with an alkylamino group in place of the methoxy moiety at C17. 17-AEP-GA is less cytotoxic than GA and remains biologically active. 17-AEP-GA was shown to induce similar tumor cell growth inhibition than 17-AAG and, unlike 17-AAG which is soluble in DMSO, to be water soluble.
1. Tian ZQ. et al., 2004. Synthesis and biological activities of novel 17-aminogeldanamycin derivatives.Bioorg Med Chem. 12(20):5317-29.
Formula
Formula: C34H50N4O8 Molecular weight: 648.78
Contents and Storage
17-AEP-GA is provided as a purple powder. 17-AEP-GA is shipped at room temperature. Store at -20°C in the dark. 17-AEP-GA is stable for 6 months when stored properly.
17-(Dimethylaminopropylamino)-17-demethoxygeldanamycin (17-DMAP-GA) belongs to a new set of geldanamycin analogues that have been synthesized based on binding affinity to Hsp90 and water solubility. 17-DMAP-GA was shown to greatly inhibit the growth of cancer cells (IC50 below 100 nM) [1]. Its binding affinity to Hsp90 was not significantly affected while its water solubility was highly improved compared to 17-AAG.
1. Tian ZQ. et al., 2004. Synthesis and biological activities of novel 17-aminogeldanamycin derivatives.Bioorg Med Chem. 12(20):5317-29.
Formula
Formula: C33H50N4O8, HCl Molecular weight: 667.23
Contents and Storage
17-DMAP-GA is provided as a purple powder. 17-DMAP-GA is shipped at room temperature. Store at -20°C in the dark. 17-DMAP-GA is stable for 6 months when stored properly.
Disclaimer: Our products are provided for research purpose only. Commercial applications may require licensing from third parties.
Note that the sequence of available ORFs provided by InvivoGen can differ from a given reference Genbank record due to genetic variations
and/or alternative splicing. Customers should verify that the version of a gene sold by InvivoGen is suitable for the customer needs.
