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
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
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11855755 | https://www.ncbi.nlm.nih.gov/pubmed/24477711
Curator's Comment: Alvespimycin (17-DMAG) is brain penetrant and CNS active in animals. No human data available.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2095165 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12725864 |
62.0 nM [EC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
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: 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%) Other AEs: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%) 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%) Sources: Page: p.701, 702Cardiac ischemia (grade 3-4, 50%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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 |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20111068
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27909289
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).
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NCI_THESAURUS |
C2516
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CHEMBL383824
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C76665
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DBSALT002385
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300000042545
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ACTIVE MOIETY
SUBSTANCE RECORD