Geldanamycin

Geldanamycin, a crystalline antimicrobial compound derived from the culture filtrates of Streptomyces hygroscopicus var. geldanus var. nova., is a potent and specific inhibitor of heat shock protein 90 (Hsp90) that specifically binds to the unique ATP binding pocket of Hsp90 in a stable and pharmacologically specific manner. As an antimicrobial agent, geldanamycin exhibits moderate activity against protozoa, bacteria and fungi as well as parasite Syphacia oblevata and cell cultures of L-1210 and KB. Recent studies have shown that geldanamycin also inhibits the function of glucocorticoid receptor and endothelium-dependent relaxation of the rat aorta, mesentery and middle artery.

Reference

Bucci M, Roviezzo F, Cicala C, Sessa WC, Cirino G. Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo. Br J Pharmacol. 2000; 131(1): 13-16.

DeBoer C, Meulman PA, Wnuk RJ, Peterson DH. Geldanamycin, a new antibiotic. J Antibiot (Tokyo). 1970; 23(9):442-447.

Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity.[Pubmed:28213093]

Toxicol Appl Pharmacol. 2017 Apr 1;320:60-72.

Despite enormous advances in remedies developed for breast cancer, an effective therapeutic strategy by targeting malignant cells with the least normal tissue toxicity is yet to be developed. Hsp90 is considered to be an important therapeutic target to inhibit cell proliferation. Geldanamycin (GDM), a potent inhibitor of Hsp90 was withdrawn from clinical trials due to its undesirable hepatotoxicity. We report a superparamagnetic iron oxide (SPION) based polymeric nanocomposite of GDM augmenting anticancer competence with decreased hepatic toxicity. The particle size of nanocomposite was ascertained to be 76+/-10nm with acceptable stability. A comparative dose dependent in vitro validation of cytotoxicity showed an enhanced cellular damage and necrosis in breast cancer (MCF-7) cell line at a low dose of 5.49nM (in GDM nanocomposite) in contrast to 20nM of pure GDM, while normal breast epithelial cells (MCF-10A) were least affected. Besides, in vivo study (in breast cancer xenografts) substantiated 2.7 fold delay in tumor progression mediated by redundancy in the downstream functions of p-Akt and MAPK-Erk leading to apoptosis with negligible hepatotoxicity. Pure GDM disrupted the function and morphology of liver with lesser therapeutic efficacy than the GDM nanocomposite. These findings deduce that GDM based polymeric magnetite nanocomposite play a vital role in efficacious therapy while vanquishing normal cells and hepatic toxicity and thereby promising it to be reinstated in clinics.

Streptomyces cameroonensis sp. nov., a Geldanamycin Producer That Promotes Theobroma cacao Growth.[Pubmed:28260703]

Microbes Environ. 2017 Mar 31;32(1):24-31.

The taxonomy of an actinobacterial strain, designated JJY4(T), was established using a polyphasic approach. JJY4(T) was isolated from the rhizosphere of Chromolaena odorata in Yaounde (Cameroon) during a project for the selection of biological control agents. Strain JJY4(T) exhibited antimicrobial activities against bacteria, fungi, and oomycetes. Strain JJY4(T) also exhibited the traits of plant growth-promoting rhizobacteria such as the solubilization of inorganic phosphate, production of siderophores and indole-3-acetic acid, and 1-aminocyclopropane-1-carboxylate deaminase activity. In planta assays performed on cocoa plantlets confirmed that strain JJY4(T) exhibited strong abilities to promote plant growth and protect against Phytophthora megakarya, the main causal agent of cocoa pod rot. The formation of rugose-ornamented spores in spiral spore chains by strain JJY4(T) is a typical feature of members found in the Streptomyces violaceusniger clade and, similar to some members of the clade, strain JJY4(T) produces Geldanamycin. A phylogenetic analysis based on 16S rRNA gene sequences confirmed this classification and suggests that strain JJY4(T) be added to the subclade constituted of the type strains Streptomyces malaysiensis DSM 41697(T) and Streptomyces samsunensis DSM 42010(T). However, DNA-DNA relatedness and physiological characteristics allowed for the differentiation of strain JJY4(T) from its closest phylogenetic relatives. Based on these results, strain JJY4(T) (=NRRL B-65369, =NBRC 112705) appears to represent a novel species in the S. violaceusniger clade for which the proposed name is Streptomyces cameroonensis sp. nov.

Mccrearamycins A-D, Geldanamycin-Derived Cyclopentenone Macrolactams from an Eastern Kentucky Abandoned Coal Mine Microbe.[Pubmed:28140487]

Angew Chem Int Ed Engl. 2017 Mar 6;56(11):2994-2998.

Four cyclopentenone-containing ansamycin polyketides (mccrearamycins A-D), and six new Geldanamycins (Gdms B-G, including new linear and mycothiol conjugates), were characterized as metabolites of Streptomyces sp. AD-23-14 isolated from the Rock Creek underground coal mine acid drainage site. Biomimetic chemical conversion studies using both simple synthetic models and Gdm D confirmed that the mccrearamycin cyclopentenone derives from benzilic acid rearrangement of 19-hydroxy Gdm, and thereby provides a new synthetic derivatization strategy and implicates a potential unique biocatalyst in mccrearamycin cyclopentenone formation. In addition to standard Hsp90alpha binding and cell line cytotoxicity assays, this study also highlights the first assessment of Hsp90alpha modulators in a new axolotl embryo tail regeneration (ETR) assay as a potential new whole animal assay for Hsp90 modulator discovery.

Inhibition of heat shock protein (Hsp) 27 potentiates the suppressive effect of Hsp90 inhibitors in targeting breast cancer stem-like cells.[Pubmed:22445681]

Biochimie. 2012 Jun;94(6):1382-9.

Heat shock protein (Hsp) 90 is an ATP-dependent chaperone and its expression has been reported to be associated with poor prognosis of breast cancer. Cancer stem cells (CSCs) are particular subtypes of cells in cancer which have been demonstrated to be important to tumor initiation, drug resistance and metastasis. In breast cancer, breast CSCs (BCSCs) are identified as CD24-CD44 + cells or cells with high intracellular aldehyde dehydrogenase activity (ALDH+). Although the clinical trials of Hsp90 inhibitors in breast cancer therapy are ongoing, the BCSC targeting effect of them remains unclear. In the present study, we discovered that the expression of Hsp90alpha was increased in ALDH + human breast cancer cells. Geldanamycin (GA), a Hsp90 inhibitor, could suppress ALDH + breast cancer cells in a dose dependent manner. We are interesting in the insufficiently inhibitory effect of low dose GA treatment. It was correlated with the upregulation of Hsp27 and Hsp70. By co-treatment with HSP inhibitors, quercetin or KNK437 potentiated BCSCs, which determined with ALDH+ population or mammosphere cells, toward GA inhibition, as well as anti-proliferation and anti-migration effects of GA. With siRNA mediated gene silencing, we found that knockdown of Hsp27 could mimic the effect of HSP inhibitors to potentiate the BCSC targeting effect of GA. In conclusion, combination of HSP inhibitors with Hsp90 inhibitors could serve as a potential solution to prevent the drug resistance and avoid the toxicity of high dose of Hsp90 inhibitors in clinical application. Furthermore, Hsp27 may play a role in chemoresistant character of BCSCs.

Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin.[Pubmed:9925731]

J Med Chem. 1999 Jan 28;42(2):260-6.

The cellular activity of several regulatory and signal transduction proteins, which depend on the Hsp90 molecular chaperone for folding, is markedly decreased by Geldanamycin and by radicicol (monorden). We now show that these unrelated compounds both bind to the N-terminal ATP/ADP-binding domain of Hsp90, with radicicol displaying nanomolar affinity, and both inhibit the inherent ATPase activity of Hsp90 which is essential for its function in vivo. Crystal structure determinations of Hsp90 N-terminal domain complexes with Geldanamycin and radicicol identify key aspects of their nucleotide mimicry and suggest a rational basis for the design of novel antichaperone drugs.

Signal-transduction cascades as targets for therapeutic intervention by natural products.[Pubmed:9807840]

Trends Biotechnol. 1998 Oct;16(10):427-33.

Many bacteria and fungi produce natural products that are toxic to other microorganisms and have a variety of physiological effects in animals. Recent studies have revealed that, in several cases, the targets of these agents are components of conserved signal-transduction cascades. This article looks at the mechanisms of action of five natural products--the immunosuppressants cyclosporin A, FK506 and rapamycin, and the antiproliferative agents wortmannin and Geldanamycin. These mechanisms reveal the importance of signal-transduction cascades as targets for therapeutic intervention and the enormous utility of studies of natural-product action in simple model genetic systems.

Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation.[Pubmed:8078881]

Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8324-8.

The molecular mechanisms by which oncogenic tyrosine kinases induce cellular transformation are unclear. Herbimycin A, Geldanamycin, and certain other benzoquinone ansamycins display an unusual capacity to revert tyrosine kinase-induced oncogenic transformation. As an approach to the study of v-src-mediated transformation, we examined ansamycin action in transformed cells and found that drug-induced reversion could be achieved without direct inhibition of src phosphorylating activity. To identify mechanisms other than kinase inhibition for drug-mediated reversion, we prepared a solid phase-immobilized Geldanamycin derivative and affinity precipitated the molecular targets with which the drug interacted. In a range of cell lines, immobilized Geldanamycin bound elements of a major class of heat shock protein (HSP90) in a stable and pharmacologically specific manner. Consistent with these binding data, we found that soluble Geldanamycin and herbimycin A inhibited specifically the formation of a previously described src-HSP90 heteroprotein complex. A related benzoquinone ansamycin that failed to revert transformed cells did not inhibit the formation of this complex. These results demonstrate that HSP participation in multimolecular complex formation is required for src-mediated transformation and can provide a target for drug modulation.

Selective Hsp90 inhibitor; breast cancer stem cell inhibitor,Geldanamycin is a natural existing HSP90 inhibitor with Kd of 1.2 μM, specifically disrupts glucocorticoid receptor (GR)/HSP association.

Geldanamycin,30562-34-6,Natural Products,HSP, buy Geldanamycin , Geldanamycin supplier , purchase Geldanamycin , Geldanamycin cost , Geldanamycin manufacturer , order Geldanamycin , high purity Geldanamycin