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Geldanamycin and derivates thereof are a family of
a benzoquinone ansamycins, antibiotics originally isolated on the basis of
their weak antibiotic activity [1] that were
subsequently shown to display potent antitumor activity.
Geldanamycin
induces the degradation of proteins that are mutated in tumor cells such as
v-src, bcr-abl and p53 preferentially over their normal cellular
counterparts. This effect is mediated via HSP90. Despite its potent
antitumor potential, Geldanamycin has several major disadvantages as a
remedy
candidate that have led to the development of Geldanamycin analogues, in
particular analogues containing a substitution on the 17 position:
17-AAG 17-DMAG and some others
History
Originally, Geldanamycin was discovered in the broth and the mycelium of
Streptomyces sp, by DeBoer et al, and was published 1n 1970 [1].
Rinehart established the structure of Geldanamycin in the same year
[2] He went on with his research on Geldanamycin biosynthesis [3],
[5]
In 1976 DeBoyer discovered a new bacterial
strain, Streptomyces hygroscopicus var. Geldanus [4],
capable of making Geldanamycin, Nigericin and two other antibiotics of
lesser importance.
From 1973 and on, numerous applied researches were
conduct, which did not yield scientific publications but rather patents on
miscellaneous semi-synthetic derivates of Geldanamycin.
In 1977 first
two papers appear which deal with the antitumor potential of Geldanamycin,
both based on in-vitro work: [6] by Rinehart, [7]
(continued in 1978: [8]), by Price PJ, Suk WA, Skeen PC,
Spahn GJ, Chirigos MA. In 1982 Tanaka et al added a single
publication, [10] again, an in-vitro work. Tanaka showed
that Geldanamycin blocked DNA synthesis rather than RNA and
protein syntheses.
Little or no work was done until 1989, when Yamaki,
Ariga [12] found some hints about potential anti-tumor
value of this compound. However they emphasized its value as a tool in
molecular biology:
Thus, Geldanamycin
should be useful to investigate the molecular mechanism of DNA
replication promoted by c-myc protein and also to distinguish the
function of c-myc protein from that of p53 protein in DNA replication.
In 1993 a major breakthrough was achieved by Whitesell L, Mimnaugh EG, De
Costa B, Myers CE, Neckers LM., who discovered the role of the HSP (heat
shock proteins) in the initiation of certain cancers.[13].
Blagosklonny showed [ 15] how Geldanamycin could prevent
restructuring of mutated cancer-relevant proteins such as p53
In 1995 Geldanamycin was ready for preclinical studies in animals. [14]
Immediately attention was paid to the hepatotoxic properties of
geldanamycin. Then it was found that derivatization of Geldanamycin at the
position 17, may lead to desired results, such as reduction of hepatotoxic
properties, alteration of solubility etc.
For example, US patent no
4261989 claims not less than 34 various derivates of geldanamycin at the
17 th position
The first publication about the 17AAG told that
17AAG had lower in vivo toxicity than Geldanamycin. Even though HSP90
affinity to 17AAG was lesser than to Geldanamycin, 17AAG and
Geldanamycin gave biologic effects in malignant cells at similar or same
concentrations.[16]
It is very interesting though
not very surprising, that next 17AAG related publication appeared only in
2000 [17]. The discoverers of 17AAG did not claimed a
patent of it.
Another important Geldanamycin derivate, 17DMAG,
appeared in 2002 [18]. This compound had better solubility
in water, that Geldanamycin.
Miscellaneous applications
[11]
Putnam et al researched phytotoxic properties of Geldanamycin and nigericin,
in 1986
Geldanamycin is a natural
product produced by Streptomyces hygroscopicus in submerged fermentation.
InvivoGen claim they make Geldanamycin from a mutant strain of
Streptomyces hygroscopicus, inactivated for the synthesis of Nigericin. The
Nigericin is an interesting compound by itself. Fermentek produces Nigericin
as a molecular biology reagent.
Fermentek claim they use no mutants,
but native unmodified strains only, as a matter of company policy.
Pharmacology
Geldanamycin binds with high affinity into the ATP
binding pocket of Hsp 90. Hsp 90 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. Hsp 90 target proteins include mutated p53, Raf-1, Akt,
ErbB2 and hypoxia-inducible factor 1a (HIF-1a). Binding of Geldanamycin
to Hsp 90 causes the destabilization and degradation of its client proteins.
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[1] DeBoer C, Meulman PA, Wnuk RJ, Peterson DH.
Geldanamycin, a new antibiotic. J Antibiot (Tokyo). 1970
Sep;23(9):442-7. No abstract available. PMID: 5459626
[2] Geldanamycin. I. Structure assignment. J Am Chem Soc.
1970 Dec 30;92(26):7591-3. No abstract available. PMID: 5490719
[3] Geldanamycin biosynthesis and carbon magnetic resonance.J Am
Chem Soc. 1974 May 15;96(10):3316-7.
[4] J Antibiot (Tokyo). 1976 Nov;29(11):1182-8. The description
and Geldanamycin production
of Streptomyces hygroscopicus var. Geldanus.
[5] Rinehart et al, Biosynthetic origin of the C2 units of
geldanamycin and distribution of label from D-[6-13C]glucose. J
Am Chem Soc. 1977 May 11;99(10):3541-4.
[6] Effects of geldanamycin and its derivatives on RNA-directed
DNA polymerase and infectivity of Rauscher leukemia virus. Cancer
Treat Rep. 1977 Aug;61(5):815-24
[7] Geldanamycin inhibition of 3-methylcholanthrene-induced rat
embryo cell transformation. Proc Soc Exp Biol Med. 1977
Sep;155(4):461-3
[8] Preferential inhibition of terminal
deoxynucleotidyltransferase activity among deoxyribonucleic acid
polymerase activities of leukemic and normal cells by geldanamycin,
streptoval C, streptovarone, and dapmavarone.
Mol Pharmacol. 1978 May;14(3):442-7
[9] Growth inhibition of virus transformed cells in vitro and
antitumor activity in vivo of geldanamycin and its derivatives.J
Antibiot (Tokyo). 1979 Aug;32(8):849-51. Sasaki K, Yasuda H,
Onodera K.
[10]Inhibition
of DNA synthesis in murine tumor cells by geldanamycin, an
antibiotic of the benzoquinoid ansamycin group.
[11] Herbicidal
effects of geldanamycin and nigericin, antibiotics from Streptomyces
hygroscopicus.
[12]Inhibition
of c-myc gene expression in murine lymphoblastoma cells by
geldanamycin and herbimycin, antibiotics of benzoquinoid ansamycin
group
[13]
Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8324-8;
Inhibition of heat shock protein HSP90-pp60v-src heteroprotein
complex formation by benzoquinone ansamycins: essential role for
stress proteins in oncogenic transformation.
[14] Preclinical
pharmacologic evaluation of geldanamycin as an antitumor agent
[15]
Geldanamycin selectively destabilizes and conformationally alters
mutated p53
[16] The
benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds
to HSP90 and shares important biologic activities with geldanamycin.
Cancer Chemother Pharmacol. 1998;42(4):273-9
Schulte TW, Neckers LM.
[17] Modulation of metastasis
phenotypes of non-small cell lung cancer cells by 17-allylamino
17-demethoxy geldanamycin.
Ann Thorac Surg. 2000 Dec;70(6):1853-60. Nguyen DM, Desai
S, Chen A, Weiser TS, Schrump DS.
[18]
Pharmacokinetics, tissue distribution, and metabolism of
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545)
in CD2F1 mice and Fischer 344 rats.
Cancer Chemother Pharmacol. 2002 Jan;49(1):7-19.
to Hsp 90 causes the destabilization and degradation of its client proteins.