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

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 11 Target ID: CHEMBL3880 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11599571	Binding Agent 1064		0.714 µM [Kd]
Heat shock protein HSP 90-beta 13 Target ID: CHEMBL4303 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11599571	Binding Agent 1064		0.152 µM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Unknown 2578

PubMed

Title	Date	PubMed
Geldanamycin, a new antibiotic.	1970 Sep	5459626
Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.	1995	7628050
p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2.	1996 Mar 1	8617772
Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway.	1996 Oct	8816498
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells.	1999 Apr-May	10401681
The benzoquinone ansamycin geldanamycin stimulates proteolytic degradation of focal adhesion kinase.	1999 Jan	9973544
Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway.	2000 Dec	11133817
Geldanamycin: the prototype of a class of antitumor drugs targeting the heat shock protein 90 family of molecular chaperones.	2001 Apr	11599571
Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90.	2001 Feb 2	11071886
Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer.	2001 Jul	11448926
Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation.	2002 Oct	12237327
ATPase inhibitors suppress actinomycin D-induced apoptosis in leukemia cells.	2002 Sep-Oct	12530016
Interaction of the PAS B domain with HSP90 accelerates hypoxia-inducible factor-1alpha stabilization.	2004	15319539
PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1alpha from pVHL-independent degradation.	2004 Apr 2	14726529
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	14656992
Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs.	2004 Mar 1	14576064
Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity.	2004 May	15141013
Src tyrosine kinase regulates CYP17 expression and androstenedione secretion in theca-enriched mouse ovarian cells.	2004 Nov	15711029
CHIP (carboxyl terminus of Hsc70-interacting protein) promotes basal and geldanamycin-induced degradation of estrogen receptor-alpha.	2005 Dec	16037132
Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation.	2005 Jun 1	15930313
15-Hydroxyprostaglandin dehydrogenase can be induced by dexamethasone and other glucocorticoids at the therapeutic level in A549 human lung adenocarcinoma cells.	2005 Mar 1	15680906
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	15781649
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	16825487
Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines.	2007 Feb	16950796
[Geldanamycin inhibits proliferation and motility of human HER2/neu-overexpressing breast cancer cell line SKBr3].	2007 Oct	17959518
Proteasome-dependent pharmacological rescue of cystic fibrosis transmembrane conductance regulator revealed by mutation of glycine 622.	2008 Apr	18230692
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	20057149
Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity.	2010 Mar	19934398
Inhibition of HSP90-dependent telomerase activity in amyloid β-induced apoptosis of cerebral endothelial cells.	2011 Aug	21520056
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
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	24211270
N-acetylcysteine prevents the geldanamycin cytotoxicity by forming geldanamycin-N-acetylcysteine adduct.	2014 Sep 5	24998639
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	25477506
Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration.	2016 Jan	26705709

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.

Name

Type

Language

GELDANAMYCIN

Common Name

English

GELDANAMYCIN [MI]

Common Name

English

NSC-122750

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C1003