GELDANAMYCIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C29H40N2O9
Molecular Weight	560.6359
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CO[C@H]1C[C@H](C)CC2=C(OC)C(=O)C=C(NC(=O)\C(C)=C\C=C[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@H]1O)C2=O

InChI

InChIKey=QTQAWLPCGQOSGP-KSRBKZBZSA-N

InChI=1S/C29H40N2O9/c1-15-11-19-25(34)20(14-21(32)27(19)39-7)31-28(35)16(2)9-8-10-22(37-5)26(40-29(30)36)18(4)13-17(3)24(33)23(12-15)38-6/h8-10,13-15,17,22-24,26,33H,11-12H2,1-7H3,(H2,30,36)(H,31,35)/b10-8-,16-9+,18-13+/t15-,17+,22+,23+,24-,26+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C29H40N2O9
Molecular Weight	560.6359
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	6 / 6
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11599571 | https://www.ncbi.nlm.nih.gov/pubmed/5459626

Geldanamycin, an antimicrobial compound, was purified in 1970 from the culture filtrates of Streptomyces hygroscopicus var. geldanus var. nova. Geldanamycin is moderately active in vitro against protozoa, bacteria, and fungi. It also has an antineoplastic effect against some cancer cells growing in culture. Molecular studies revealed the binding of geldanamycin to members of the heat shock protein 90 (HSP90) family of molecular chaperones. Interference with the function of these HSPs seems to be the major mechanism of action of geldanamycin.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Heat shock protein HSP 90-alpha 12 Target ID: CHEMBL3880 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11599571	Binding Agent 1076		0.714 µM [Kd]
Heat shock protein HSP 90-beta 14 Target ID: CHEMBL4303 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11599571	Binding Agent 1076		0.152 µM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Unknown 2596

PubMed

Title	Date	PubMed
Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration.	2016-01	26705709
The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells.	2015-01-16	25477506
N-acetylcysteine prevents the geldanamycin cytotoxicity by forming geldanamycin-N-acetylcysteine adduct.	2014-09-05	24998639
Potential role of HSP90 in mediating the interactions between estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) signaling pathways.	2014-04-07	24487124
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013-12	24052561
Protein-selective capture to analyze electrophile adduction of hsp90 by 4-hydroxynonenal.	2011-08-15	21749116
Inhibition of HSP90-dependent telomerase activity in amyloid β-induced apoptosis of cerebral endothelial cells.	2011-08	21520056
Pharmacogenomic approach reveals a role for the x(c)- cystine/glutamate antiporter in growth and celastrol resistance of glioma cell lines.	2010-03	20007406
Geldanamycin induces production of heat shock protein 70 and partially attenuates ototoxicity caused by gentamicin in the organ of Corti explants.	2009-09-02	19723345
Enhanced clonogenic survival induced by protein tyrosine phosphatase (PTP) inhibition after Cr(VI) exposure is mediated by c-Raf and Ras activity.	2009-05	19167484
Proteasome-dependent pharmacological rescue of cystic fibrosis transmembrane conductance regulator revealed by mutation of glycine 622.	2008-04	18230692
[Geldanamycin inhibits proliferation and motility of human HER2/neu-overexpressing breast cancer cell line SKBr3].	2007-10	17959518
Resistance to geldanamycin-induced apoptosis in differentiated neuroblastoma SH-SY5Y cells.	2007-03-06	17293044
Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue.	2007-01	17024233
The bioreduction of a series of benzoquinone ansamycins by NAD(P)H:quinone oxidoreductase 1 to more potent heat shock protein 90 inhibitors, the hydroquinone ansamycins.	2006-10	16825487
Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection.	2006-09	16311509
Effects of geldanamycin on HIF-1alpha mediated angiogenesis and invasion in prostate cancer cells.	2006	16432534
Effects of organochlorine insecticides on MAP kinase pathways in human HaCaT keratinocytes: key role of reactive oxygen species.	2005-08	15888667
Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation.	2005-06-01	15930313
Interleukin-1beta attenuates beta-very low-density lipoprotein uptake and its receptor expression in vascular smooth muscle cells.	2005-04	15808840
Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro.	2005-03-15	15781649
15-Hydroxyprostaglandin dehydrogenase can be induced by dexamethasone and other glucocorticoids at the therapeutic level in A549 human lung adenocarcinoma cells.	2005-03-01	15680906
Src tyrosine kinase regulates CYP17 expression and androstenedione secretion in theca-enriched mouse ovarian cells.	2004-11	15711029
Autocrine extracellular signal-regulated kinase (ERK) activation in normal human keratinocytes: metalloproteinase-mediated release of amphiregulin triggers signaling from ErbB1 to ERK.	2004-09	15254267
Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity.	2004-05	15141013
PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1alpha from pVHL-independent degradation.	2004-04-02	14726529
Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs.	2004-03-01	14576064
Hair growth induction by the Tellurium immunomodulator AS101: association with delayed terminal differentiation of follicular keratinocytes and ras-dependent up-regulation of KGF expression.	2004-02	14656992
Interaction of the PAS B domain with HSP90 accelerates hypoxia-inducible factor-1alpha stabilization.	2004	15319539
Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion.	2003-08	12811834
Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG.	2003-06-27	12775586
PTHrP [67-86] regulates the expression of stress proteins in breast cancer cells inducing modifications in urokinase-plasminogen activator and MMP-1 expression.	2003-06-15	12724357
Functional analysis of murine aryl hydrocarbon (AH) receptors defective in nuclear import: impact on AH receptor degradation and gene regulation.	2003-03	12606767
Geldanamycin inhibits the production of inflammatory cytokines in activated macrophages by reducing the stability and translation of cytokine transcripts.	2003-02	12571865
ATPase inhibitors suppress actinomycin D-induced apoptosis in leukemia cells.	2003-01-18	12530016
Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation.	2002-10	12237327
Involvement of human heat shock protein 90 alpha in nicotine-induced apoptosis.	2002-07-01	12115584
Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells.	2002-05-01	11980636
Suppressive effects of ansamycins on inducible nitric oxide synthase expression and the development of experimental autoimmune encephalomyelitis.	2002-02-15	11835313
Geldanamycin inhibits NF-kappaB activation and interleukin-8 gene expression in cultured human respiratory epithelium.	2001-07	11472980
Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease.	2001-06-01	11406612
Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90.	2001-02-02	11071886
Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway.	2000-12	11133817
Geldanamycin induces heat shock protein expression through activation of HSF1 in K562 erythroleukemic cells.	1999-10	10632574
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells.	1999-07-13	10401681
Alterations in the growth factor signal transduction pathways and modulators of the cell cycle in endocervical cells from macaques exposed to TCDD.	1998-08	9707505
Use of c-Src and c-Fos knockout mice for the studies on the role of c-Src kinase signaling in the expression of toxicity of TCDD.	1998	9664232
Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway.	1996-10	8816498
Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells.	1996-06	8776730
p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2.	1996-03-01	8617772

Patents

Sample Use Guides

In Vivo Use Guide

Maximum tolerated doses were approximately 20 mg/kg for the mice and 4 mg/kg for the dog.

Route of Administration: Intravenous

In Vitro Use Guide

The mechanism of action of geldanamycin was investigated with murine lymphoblastoma L5178Y cells. The agent inhibited the cell growth at concentrations over 0.01 micrograms/ml. Geldanamycin blocked DNA polymerase alpha more markedly than beta and gamma. The degree of inhibition depended upon concentrations of the enzyme but not upon those of template, suggesting a drug-enzyme interaction. IC50 for DNA polymerase alpha was 10 micrograms/ml and for DNA polymerase beta 100 micrograms/ml at low concentrations of enzyme. The inhibition of DNA polymerase alpha by the antibiotic was non-competitive and Ki was 20 microM.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 19:44:07 GMT 2025` Edited by `admin` on `Mon Mar 31 19:44:07 GMT 2025`
Record UNII	Z3K3VJ16KU
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NSC-122750

Preferred Name

English

GELDANAMYCIN

Common Name

English

GELDANAMYCIN [MI]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1003