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Details

Stereochemistry ABSOLUTE
Molecular Formula C32H48N4O8.ClH
Molecular Weight 653.206
Optical Activity UNSPECIFIED
Defined Stereocenters 6 / 6
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ALVESPIMYCIN HYDROCHLORIDE

SMILES

Cl.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=DFSYBWLNYPEFJK-IHLRWNDRSA-N
InChI=1S/C32H48N4O8.ClH/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);1H/b11-9-,19-10+,21-16+;/t18-,20+,25+,26+,28-,30+;/m1./s1

HIDE SMILES / InChI

Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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

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

Curator's Comment: Alvespimycin (17-DMAG) is brain penetrant and CNS active in animals. No human data available.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
62.0 nM [EC50]
Conditions
Doses

Doses

DosePopulationAdverse 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: 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: 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: 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: 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: Page: p.702
DLT: Diarrhea...
Dose limiting toxicities:
Diarrhea (grade 3-4, 9%)
Sources: 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: 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: 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: 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: 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: Page: p.701, 702
AEs

AEs

AESignificanceDosePopulation
Anorexia grade 2, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Fever grade 2, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Nausea grade 2, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Vomiting grade 2, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Blood creatinine increased grade 3, 25%
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: 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: Page: p.5, 6
Fatigue grade 3, 25%
DLT
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: 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: Page: p.5, 6
Hypoalbuminemia grade 3, 25%
DLT
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: 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: Page: p.5, 6
Acidosis grade 3, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Dehydration grade 3, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Diarrhea grade 3, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Hyponatremia grade 3, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
AST increased grade 4, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Acute hypotension grade 4, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Acute renal failure grade 5, 25%
DLT, Disc. AE
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: 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: Page: p.5, 6
Diarrhea grade 3-4, 9%
DLT
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: 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: Page: p.702
Cardiac ischemia grade 3-4, 50%
DLT
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: 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: Page: p.701, 702
Acute myocardial infarction grade 5, 50%
DLT, Disc. AE
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: 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: Page: p.701, 702
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90.
2003 Apr
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
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
Heat shock protein inhibitors, 17-DMAG and KNK437, enhance arsenic trioxide-induced mitotic apoptosis.
2009 Apr 15
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
Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta.
2010 Jan 20
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
2011 Jul
Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants.
2012 Sep 1
Patents

Patents

Sample Use Guides

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
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 15:52:51 UTC 2023
Edited
by admin
on Fri Dec 15 15:52:51 UTC 2023
Record UNII
612K359T69
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ALVESPIMYCIN HYDROCHLORIDE
USAN   WHO-DD  
USAN  
Official Name English
KOS-1022
Code English
ALVESPIMYCIN HYDROCHLORIDE [USAN]
Common Name English
BMS-826476
Code 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 HYDROCHLORIDE
Common Name English
ALVESPIMYCIN HCL
Common Name English
Alvespimycin hydrochloride [WHO-DD]
Common Name English
GELDANAMYCIN, 17-DEMETHOXY-17-((2-(DIMETHYLAMINO)ETHYL)AMINO)-, MONOHYDROCHLORIDE
Common Name English
17-DMAG HCL
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C2516
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
Code System Code Type Description
CAS
467214-21-7
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
PUBCHEM
9852573
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
FDA UNII
612K359T69
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
USAN
WW-59
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
ChEMBL
CHEMBL383824
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
EPA CompTox
DTXSID40431773
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
NCI_THESAURUS
C76665
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
DRUG BANK
DBSALT002385
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
SMS_ID
300000042545
Created by admin on Fri Dec 15 15:52:51 UTC 2023 , Edited by admin on Fri Dec 15 15:52:51 UTC 2023
PRIMARY
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