ALVESPIMYCIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C32H48N4O8
Molecular Weight	616.7455
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(NCCN(C)C)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=KUFRQPKVAWMTJO-LMZWQJSESA-N

InChI=1S/C32H48N4O8/c1-18-14-22-27(34-12-13-36(5)6)24(37)17-23(29(22)39)35-31(40)19(2)10-9-11-25(42-7)30(44-32(33)41)21(4)16-20(3)28(38)26(15-18)43-8/h9-11,16-18,20,25-26,28,30,34,38H,12-15H2,1-8H3,(H2,33,41)(H,35,40)/b11-9-,19-10+,21-16+/t18-,20+,25+,26+,28-,30+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C32H48N4O8
Molecular Weight	616.7455
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/12725864 | https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=378203 | https://www.ncbi.nlm.nih.gov/pubmed/22781552 | https://www.ncbi.nlm.nih.gov/pubmed/20111068 | http://adisinsight.springer.com/drugs/800021183

Alvespimycin (17-desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin) (17-DMAG; NSC 707545) is an inhibitor of the molecular chaperone heat shock protein HSP90. Alvespimycin is a derivative of antineoplastic benzoquinone antibiotic geldanamycin. Alvespimycin binds to HSP90, a chaperone protein that aids in the assembly, maturation and folding of proteins. Subsequently, the function of Hsp90 is inhibited, leading to the degradation and depletion of its client proteins such as kinases and transcription factors involved with cell cycle regulation and signal transduction. Alvespimycin was studied in clinical trials for the treatment of solid tumors and hematologic malignancies however its development was discontinued.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Heat shock protein HSP90 35 Target ID: CHEMBL2095165 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12725864	Inhibitor 8297		62.0 nM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Solid tumors 145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22450873 https://www.ncbi.nlm.nih.gov/pubmed/22781552	Primary		Phase II 1132	Unknown Approved Use Unknown
Hematologic malignancies 19 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26764527 https://www.ncbi.nlm.nih.gov/pubmed/20111068	Primary		Phase I 428	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
106 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 106 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 106 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/21278242 Page: p.5, 6	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/21278242 Page: p.5, 6	DLT: Acidosis, Nausea... Other AEs: Blood creatinine increased... Dose limiting toxicities: Acidosis (grade 3, 25%) Nausea (grade 2, 25%) Hyponatremia (grade 3, 25%) Diarrhea (grade 3, 25%) Anorexia (grade 2, 25%) Dehydration (grade 3, 25%) Vomiting (grade 2, 25%) AST increased (grade 4, 25%) Acute hypotension (grade 4, 25%) Fatigue (grade 3, 25%) Fever (grade 2, 25%) Hypoalbuminemia (grade 3, 25%) Acute renal failure (grade 5, 25%) Other AEs: Blood creatinine increased (grade 3, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/21278242 Page: p.5, 6
24 mg/m2 2 times / week multiple, intravenous MTD Dose: 24 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 24 mg/m2, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/20111068 Page: p.702	unhealthy, ADULT n = 11 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 11 Sources: https://pubmed.ncbi.nlm.nih.gov/20111068 Page: p.702	DLT: Diarrhea... Dose limiting toxicities: Diarrhea (grade 3-4, 9%) Sources: https://pubmed.ncbi.nlm.nih.gov/20111068 Page: p.702
80 mg/m2 1 times / week multiple, intravenous MTD Dose: 80 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/21278242 Page: p.6	unhealthy, ADULT n = 8 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/21278242 Page: p.6	Sources: https://pubmed.ncbi.nlm.nih.gov/21278242 Page: p.6
32 mg/m2 2 times / week multiple, intravenous Studied dose Dose: 32 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 32 mg/m2, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/20111068 Page: p.701, 702	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/20111068 Page: p.701, 702	DLT: Acute myocardial infarction, Cardiac ischemia... Dose limiting toxicities: Acute myocardial infarction (grade 5, 50%) Cardiac ischemia (grade 3-4, 50%) Sources: https://pubmed.ncbi.nlm.nih.gov/20111068 Page: p.701, 702

AEs

Sourcing

Vendor/Aggregator	ID	URL
AK Scientific, Inc. (AKSCI)	X8446	http://www.aksci.com/item_detail.php?cat=X8446
Achemtek	0101-002334	http://www.achemtek.com/467214-20-6
Acorn PharmaTech	ACN-046374	http://www.acornpharmatech.com/
Active Biopharma	ABP000223	http://www.activebiopharma.com/150270-08-9
Active Biopharma	ABP000584	http://www.activebiopharma.com/467214-21-7
Aurora Fine Chemicals LLC	A13.105.467	http://online.aurorafinechemicals.com/info?ID=A13.105.467
Aurum Pharmatech LLC	W-5374	http://www.Aurumpharmatech.com/Product/ProductDetails/W_5374
AvaChem Scientific	6006	https://www.avachem.com/productSearch.asp?6006
BOC Sciences	150270-08-9	https://www.bocsci.com/17-dimethylaminoethylamino-17-demethoxygeldanamycin-cas-150270-08-9-item-122708.html
BioCrick	BCC1346	http://www.biocrick.com/Alvespimycin-BCC1346.html
Chem Scene	CS-0912	http://www.chemscene.com/467214-20-6.html
ChemMol	99046992	http://www.chemmol.com/chemmol/99046992.html
ChemShuttle	159942	http://www.chemshuttle.com/catalogsearch/result/?q=467214-20-6&cat=
Chemspace	CSSB00116207116	https://chem-space.com/CSSB00116207116
DC Chemicals	DC36820	http://www.dcchemicals.com//product_show-Alvespimycin.html
Excenen	EX-A1103	http://www.excenen.com/searchresultlist.php?id=467214-20-6
Hairui	HR116175	http://www.hairuichem.com/en/product/467214-20-6.html
Matrix Scientific	89480	https://www.matrixscientific.com/089480.html
MedChem Express	HY-10389	https://www.medchemexpress.com/alvespimycin.html
MolPort	MolPort-006-666-027	https://www.molport.com/shop/molecule-link/MolPort-006-666-027
MuseChem	I003618	https://www.musechem.com/product/I003618.html
MuseChem	M097169	https://www.musechem.com/product/M097169.html
OChem	26905	http://www.ocheminc.com/index.php?act=psearch&pid=214D206
Oakwood	M03709	http://www.oakwoodchemical.com/ProductsList.aspx?CategoryID=-2&txtSearch=128507&ExtHyperLink=1
Smolecule	S518217	http://www.smolecule.com/products/s518217
THE BioTek	bt-258596	https://www.thebiotek.com/product/inhibitors/bt-258596
abcr GmbH	AB200576	http://www.abcr.com/shop/en/AB200576
eNovation Chemicals	D567341	https://www.enovationchem.com/ProductDetails.asp?ProductID=D567341
eNovation Chemicals	Y1012794	https://www.enovationchem.com/ProductDetails.asp?ProductID=Y1012794

PubMed

Title	Date	PubMed
Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90.	2003 Apr	12725864
Schedule-dependent synergy between the heat shock protein 90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and doxorubicin restores apoptosis to p53-mutant lymphoma cell lines.	2006 Nov 1	17085670
Heat shock protein inhibitors, 17-DMAG and KNK437, enhance arsenic trioxide-induced mitotic apoptosis.	2009 Apr 15	19371599
Co-treatment with heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and vorinostat: a highly active combination against human mantle cell lymphoma (MCL) cells.	2009 Jul	19440035

Patents

Sample Use Guides

In Vivo Use Guide

Phase 1 study. Patients with advanced acute myeloid leukemia (AML) received escalating doses of intravenous alvespimycin (8-32 mg/m(2)), twice weekly, for 2 of 3 weeks. Alvespimycin was well tolerated; the maximum-tolerated dose was 24 mg/m(2) twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m(2) (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C(max) and area under the curve (AUC) from 8 to 32 mg/m(2) and minor accumulation upon repeated doses. Recommended phase 2 dose is 24 mg/m(2).

Route of Administration: Intravenous

In Vitro Use Guide

One hepatic cell line (L02) and two HCC cell lines (Huh7 and HepG2) were heated at 42 °C for 0, 0.5 or 4 h with or without 100 nM alvespimycin (17-DMAG).

Substance Class	Chemical Created by `admin` on `Fri Dec 15 16:25:37 GMT 2023` Edited by `admin` on `Fri Dec 15 16:25:37 GMT 2023`
Record UNII	001L2FE0M3
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ALVESPIMYCIN

Official Name

English

Alvespimycin [WHO-DD]

Common Name

English

alvespimycin [INN]

Common Name

English

(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-((2-(DIMETHYLAMINO)ETHYL)AMINO)-13-HYDROXY-8,14-DIMETHOXY-4,10,12,16-TETRAMETHYL-3,20,22-TRIOXO-2-AZABICYCLO(16.3.1)DOCOSA-1(21),4,6,10,18-PENTAEN-9-YL CARBAMATE

Common Name

English

GELDANAMYCIN, 17-DEMETHOXY-17-((2-(DIMETHYLAMINO)ETHYL)AMINO)-

Common Name

English

NSC-707545

Code

English

DMAG

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2516