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
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
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 |
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Target ID: CHEMBL3880 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11599571 |
0.714 µM [Kd] | ||
Target ID: CHEMBL4303 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11599571 |
0.152 µM [Kd] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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PubMed
Title | Date | PubMed |
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Geldanamycin, a new antibiotic. | 1970 Sep |
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Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. | 1995 |
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p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2. | 1996 Mar 1 |
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Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. | 1996 Oct |
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells. | 1999 Apr-May |
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The benzoquinone ansamycin geldanamycin stimulates proteolytic degradation of focal adhesion kinase. | 1999 Jan |
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Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway. | 2000 Dec |
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Geldanamycin: the prototype of a class of antitumor drugs targeting the heat shock protein 90 family of molecular chaperones. | 2001 Apr |
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Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. | 2001 Feb 2 |
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Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer. | 2001 Jul |
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Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation. | 2002 Oct |
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ATPase inhibitors suppress actinomycin D-induced apoptosis in leukemia cells. | 2002 Sep-Oct |
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Interaction of the PAS B domain with HSP90 accelerates hypoxia-inducible factor-1alpha stabilization. | 2004 |
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PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1alpha from pVHL-independent degradation. | 2004 Apr 2 |
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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 Feb |
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Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs. | 2004 Mar 1 |
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Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. | 2004 May |
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Src tyrosine kinase regulates CYP17 expression and androstenedione secretion in theca-enriched mouse ovarian cells. | 2004 Nov |
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CHIP (carboxyl terminus of Hsc70-interacting protein) promotes basal and geldanamycin-induced degradation of estrogen receptor-alpha. | 2005 Dec |
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Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation. | 2005 Jun 1 |
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15-Hydroxyprostaglandin dehydrogenase can be induced by dexamethasone and other glucocorticoids at the therapeutic level in A549 human lung adenocarcinoma cells. | 2005 Mar 1 |
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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 Mar 15 |
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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 Oct |
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Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines. | 2007 Feb |
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[Geldanamycin inhibits proliferation and motility of human HER2/neu-overexpressing breast cancer cell line SKBr3]. | 2007 Oct |
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Proteasome-dependent pharmacological rescue of cystic fibrosis transmembrane conductance regulator revealed by mutation of glycine 622. | 2008 Apr |
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The inhibitory mechanisms of the tyrosine kinase inhibitors herbimycin a, genistein, and tyrphostin B48 with regard to the function of the aryl hydrocarbon receptor in Caco-2 cells. | 2010 |
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Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity. | 2010 Mar |
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Inhibition of HSP90-dependent telomerase activity in amyloid β-induced apoptosis of cerebral endothelial cells. | 2011 Aug |
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Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. | 2013 Dec |
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The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide. | 2014 Jan 1 |
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N-acetylcysteine prevents the geldanamycin cytotoxicity by forming geldanamycin-N-acetylcysteine adduct. | 2014 Sep 5 |
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The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells. | 2015 Jan 16 |
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Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. | 2016 Jan |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/7628050/
Curator's Comment: Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/6897401
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.
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C1003
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METABOLITE (PARENT)
METABOLITE (PARENT)
SUBSTANCE RECORD