U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

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 of ALVESPIMYCIN

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

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
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 16:25:37 UTC 2023
Edited
by admin
on Fri Dec 15 16:25:37 UTC 2023
Record UNII
001L2FE0M3
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ALVESPIMYCIN
INN   WHO-DD  
INN  
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
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
Code System Code Type Description
NCI_THESAURUS
C38142
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
INN
8811
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
PUBCHEM
5288674
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
FDA UNII
001L2FE0M3
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
NSC
707545
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
EPA CompTox
DTXSID00963646
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
MESH
C448659
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
CHEBI
65324
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
WIKIPEDIA
17-Dimethylaminoethylamino-17-demethoxygeldanamycin
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
SMS_ID
100000127463
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
DRUG BANK
DB12442
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
CAS
467214-20-6
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
ChEMBL
CHEMBL383824
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
EVMPD
SUB33529
Created by admin on Fri Dec 15 16:25:37 UTC 2023 , Edited by admin on Fri Dec 15 16:25:37 UTC 2023
PRIMARY
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