RETASPIMYCIN HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C31H45N3O8.ClH
Molecular Weight	624.165
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.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=OIRUWDYJGMHDHJ-AFXVCOSJSA-N

InChI=1S/C31H45N3O8.ClH/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);1H/b11-9-,18-10+,20-15+;/t17-,19+,24+,25+,27-,29+;/m1./s1

HIDE SMILES / InChI

Description
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
Heat shock protein HSP90 35 Target ID: CHEMBL2095165 Sources: http://www.ncbi.nlm.nih.gov/pubmed/17090671	Inhibitor 8297		63.0 nM [EC50]

Conditions

Condition	Modality	Highest Phase	Product
Gastrointestinal stromal tumor 20 Sources: https://clinicaltrials.gov/ct2/show/NCT00688766	Primary	Phase III 656	Unknown Approved Use Unknown
Prostate cancer 178 Sources: https://clinicaltrials.gov/ct2/show/NCT00564928	Primary	Phase II 1132	Unknown Approved Use Unknown
Advanced dedifferentiated liposarcoma 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00969917	Primary	Phase II 1132	Unknown Approved Use Unknown
KRAS mutant non-small cell lung cancer 2 Sources: https://clinicaltrials.gov/ct2/show/NCT01427946	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

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

T_1/2

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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 Page: p.6	DLT: headache, myalgia... Dose limiting toxicities: headache (grade 3, 16.7%) myalgia (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/24045182 Page: p.6
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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 Page: p.4	Disc. AE: ALT increased, Hepatic failure... AEs leading to discontinuation/dose reduction: ALT increased (grade 3, 5.3%) Hepatic 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%) Sources: https://pubmed.ncbi.nlm.nih.gov/21762967 Page: p.4
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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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%) Hepatic failure (grade 5, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/24045182 Page: p.6, 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/21762967 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 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: https://pubmed.ncbi.nlm.nih.gov/24045182 Page: p.6, 7

Sourcing

Vendor/Aggregator	ID	URL
AbMole Bioscience	M3683	http://www.abmole.com/products/retaspimycin.html
Achemtek	0102-013797	http://www.achemtek.com/857402-23-4
Alsachim	4612	http://www.alsachim.com/product-C5959-glo.bal-view.html
ApexBio Technology	A3756	http://www.apexbt.com/retaspimycin.html
BOC Sciences	857402-23-4	https://www.bocsci.com/retaspimycin-cas-857402-23-4-item-99330.html
BioChemPartner	BCP06481	http://www.biochempartner.com/857402-23-4-BCP06481
BioCrick	BCC1889	http://www.biocrick.com/Retaspimycin-BCC1889.html
Chem Scene	CS-0651	http://www.chemscene.com/857402-23-4.html
ChemMol	49418536	http://www.chemmol.com/chemmol/49418536.html
Clearsynth	CS-EK-02070	https://www.clearsynth.com/en/CSEK02070.html
MedChem Express	HY-15263	https://www.medchemexpress.com/retaspimycin.html
MuseChem	I005151	https://www.musechem.com/product/I005151.html
OChem	29906	http://www.ocheminc.com/index.php?act=psearch&pid=402R234
Smolecule	S639259	https://www.smolecule.com/products/s639259
THE BioTek	bt-341427	https://www.thebiotek.com/product/others/bt-341427
eNovation Chemicals	D680329	https://www.enovationchem.com/ProductDetails.asp?ProductID=D680329

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	16854066
Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.	2006 Nov 14	17090671

Patents

Sample Use Guides

In Vivo Use Guide

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

Human liver microsomes were incubated for 1 h at 37°C with 50 ug/ml Retaspimycin (IPI-504)

Name

Type

Language

RETASPIMYCIN HYDROCHLORIDE

Official Name

English

Retaspimycin hydrochloride [WHO-DD]

Common Name

English

IPI-504 HYDROCHLORIDE

Code

English

RETASPIMYCIN HYDROCHLORIDE [USAN]

Common Name

English

(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13,20,22-TRIHYDROXY-8,14-DIMETHOXY-4,10,12,16- TETRAMETHYL-3-OXO-19-(PROP-2-ENYLAMINO)-2-AZABICYCLO(16.3.1)DOCOSA- 1(21),4,6,10,18(22),19-HEXEN-9-YL CARBAMATE HYDROCHLORIDE

Common Name

English

RETASPIMYCIN HYDROCHLORIDE [MI]

Common Name

English

RETASPIMYCIN HCL

Common Name

English

GELDANAMYCIN, 18,21-DIDEHYDRO-17-DEMETHOXY-18,21-DIDEOXO-18,21-DIHYDROXY-17-(2- PROPENYLAMINO)-, MONOHYDROCHLORIDE

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

260608