Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C31H45N3O8 |
Molecular Weight | 587.7043 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 6 / 6 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CO[C@H]1C[C@H](C)CC2=C(O)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)=CC(O)=C2NCC=C
InChI
InChIKey=OAKGNIRUXAZDQF-TXHRRWQRSA-N
InChI=1S/C31H45N3O8/c1-8-12-33-26-21-13-17(2)14-25(41-7)27(36)19(4)15-20(5)29(42-31(32)39)24(40-6)11-9-10-18(3)30(38)34-22(28(21)37)16-23(26)35/h8-11,15-17,19,24-25,27,29,33,35-37H,1,12-14H2,2-7H3,(H2,32,39)(H,34,38)/b11-9-,18-10+,20-15+/t17-,19+,24+,25+,27-,29+/m1/s1
DescriptionSources: http://www.ncbi.nlm.nih.gov/pubmed/17090671Curator's Comment: Description was created based on several sources, including http://www.gistsupport.org/treatments-for-gist/emerging-treatments/hsp90-inhibitors/ipi-504-retaspimycin.php and https://newdrugapprovals.org/2015/10/27/ipi-504-retaspamycin-retaspimycin/
Sources: http://www.ncbi.nlm.nih.gov/pubmed/17090671
Curator's Comment: Description was created based on several sources, including http://www.gistsupport.org/treatments-for-gist/emerging-treatments/hsp90-inhibitors/ipi-504-retaspimycin.php and https://newdrugapprovals.org/2015/10/27/ipi-504-retaspamycin-retaspimycin/
Retaspimycin (IPI-504) was previously under development by manufacturer Infinity Pharmaceuticals in conjunction with MedImmune, a part of AstraZeneca. Retaspimycin is a small-molecule inhibitor of heat shock protein 90 (HSP90) with antiproliferative and antineoplastic activities. Retaspimycin binds to and inhibits the cytosolic chaperone functions of HSP90, which maintains the stability and functional shape of many oncogenic signaling proteins and may be overexpressed or overactive in tumor cells. Retaspimycin-mediated inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, which may result in the induction of apoptosis. Orphan drug designation was assigned to the compound by the FDA for the treatment of gastrointestinal stromal cancer (GIST). Infinity Pharmaceuticals has discontinued the development of retaspimycin (IPI-504) an inhibitor of the HSP-90) complex, for the treatment of cancer due to lack of efficacy in 1913.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2095165 Sources: http://www.ncbi.nlm.nih.gov/pubmed/17090671 |
63.0 nM [EC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
7800 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21762967 |
400 mg/m² single, intravenous dose: 400 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
RETASPIMYCIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
4637 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21851215 |
400 mg/m² 2 times / week single, intravenous dose: 400 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
RETASPIMYCIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
11712 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21762967 |
400 mg/m² single, intravenous dose: 400 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
RETASPIMYCIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
5030 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21851215 |
400 mg/m² 2 times / week single, intravenous dose: 400 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
RETASPIMYCIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2.27 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21762967 |
400 mg/m² single, intravenous dose: 400 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
RETASPIMYCIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
1.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21851215 |
400 mg/m² 2 times / week single, intravenous dose: 400 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
RETASPIMYCIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
500 mg/m2 2 times / week multiple, intravenous Highest studied dose Dose: 500 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 500 mg/m2, 2 times / week Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: sarcoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
DLT: headache, myalgia... Dose limiting toxicities: headache (grade 3, 16.7%) Sources: Page: p.6myalgia (grade 3, 16.7%) |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.4 |
unhealthy, ADULT n = 19 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: Page: p.4 |
Disc. AE: ALT increased, Hepatic failure... AEs leading to discontinuation/dose reduction: ALT increased (grade 3, 5.3%) Sources: Page: p.4Hepatic failure (grade 5, 5.3%) Hyperglycemia (grade 5, 5.3%) ketoacidosis (grade 5, 5.3%) Multi-organ failure (grade 5, 5.3%) AST increased (grade 3, 5.3%) |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.6, 7 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: sarcoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6, 7 |
DLT: Intracerebral hemorrhage... Other AEs: Acute renal failure, Hepatic failure... Dose limiting toxicities: Intracerebral hemorrhage (grade 5, 16.7%) Other AEs:Acute renal failure (grade 5, 16.7%) Sources: Page: p.6, 7Hepatic failure (grade 5, 16.7%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
headache | grade 3, 16.7% DLT |
500 mg/m2 2 times / week multiple, intravenous Highest studied dose Dose: 500 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 500 mg/m2, 2 times / week Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: sarcoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
myalgia | grade 3, 16.7% DLT |
500 mg/m2 2 times / week multiple, intravenous Highest studied dose Dose: 500 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 500 mg/m2, 2 times / week Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: sarcoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
ALT increased | grade 3, 5.3% Disc. AE |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.4 |
unhealthy, ADULT n = 19 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: Page: p.4 |
AST increased | grade 3, 5.3% Disc. AE |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.4 |
unhealthy, ADULT n = 19 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: Page: p.4 |
Hepatic failure | grade 5, 5.3% Disc. AE |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.4 |
unhealthy, ADULT n = 19 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: Page: p.4 |
Hyperglycemia | grade 5, 5.3% Disc. AE |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.4 |
unhealthy, ADULT n = 19 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: Page: p.4 |
Multi-organ failure | grade 5, 5.3% Disc. AE |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.4 |
unhealthy, ADULT n = 19 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: Page: p.4 |
ketoacidosis | grade 5, 5.3% Disc. AE |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.4 |
unhealthy, ADULT n = 19 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: Page: p.4 |
Acute renal failure | grade 5, 16.7% | 400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.6, 7 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: sarcoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6, 7 |
Hepatic failure | grade 5, 16.7% | 400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.6, 7 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: sarcoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6, 7 |
Intracerebral hemorrhage | grade 5, 16.7% DLT, Disc. AE |
400 mg/m2 2 times / week multiple, intravenous MTD Dose: 400 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 2 times / week Sources: Page: p.6, 7 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: sarcoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6, 7 |
PubMed
Title | Date | PubMed |
---|---|---|
Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. | 2006 Jul 27 |
|
Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. | 2006 Nov 14 |
|
HSP90 inhibition enhances antimitotic drug-induced mitotic arrest and cell death in preclinical models of non-small cell lung cancer. | 2014 |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24045182
Retaspimycin (IPI-504) was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off.
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: http://www.ncbi.nlm.nih.gov/pubmed/17090671
Human liver microsomes were incubated for 1 h at 37°C with 50 ug/ml Retaspimycin (IPI-504)
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Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C2516
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FDA ORPHAN DRUG |
242907
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CHEMBL1184904
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DTXSID70870378
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C80378
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9000
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11534420
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71956
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100000175017
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m9552
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857402-23-4
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TT-114
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71975
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)