TRABECTEDIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C39H43N3O11S
Molecular Weight	761.837
Optical Activity	UNSPECIFIED
Defined Stereocenters	7 / 7
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12[C@@H]3SC[C@]4(NCCC5=CC(O)=C(OC)C=C45)C(=O)OC[C@H](N1[C@@H](O)[C@@H]6CC7=CC(C)=C(OC)C(O)=C7[C@H]2N6C)C8=C3C(OC(C)=O)=C(C)C9=C8OCO9

InChI

InChIKey=PKVRCIRHQMSYJX-AIFWHQITSA-N

InChI=1S/C39H43N3O11S/c1-16-9-20-10-22-37(46)42-23-13-50-38(47)39(21-12-25(48-5)24(44)11-19(21)7-8-40-39)14-54-36(30(42)29(41(22)4)26(20)31(45)32(16)49-6)28-27(23)35-34(51-15-52-35)17(2)33(28)53-18(3)43/h9,11-12,22-23,29-30,36-37,40,44-46H,7-8,10,13-15H2,1-6H3/t22-,23-,29+,30+,36+,37-,39+/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20647340 | http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207953s001lbl.pdf

Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata. Trabectedin was approved for the treatment of liposarcoma or leiomyosarcoma (USA and Europe) and ovarian cancer (only in Europe). Trabectedin exerts its anti-cancer action by binding guanine residues in the minor groove of DNA. The binding prevents DNA from interacting with transcription factors and the reparation system and results in perturbation of the cell cycle and eventual cell death.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278 Target ID: DNA Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207953s001lbl.pdf	Binding Agent 1064

Conditions

Condition	Modality	Highest Phase	Product
Liposarcoma 6 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207953s001lbl.pdf	Primary	Approved 8429	YONDELIS Approved Use YONDELIS is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Launch Date 2015
Leiomyosarcoma 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207953s001lbl.pdf	Primary	Approved 8429	YONDELIS Approved Use YONDELIS is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Launch Date 2015
Ovarian cancer 157 Sources: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000773/WC500045833.pdf	Primary	Approved 8429	YONDELIS Approved Use Yondelis is used to treat adults with two types of cancer: advanced soft-tissue sarcoma, when treatment with anthracyclines and ifosfamide have stopped working, or in patients who cannot be given these medicines; ovarian cancer that has relapsed and is sensitive to medicines containing platinum (in combination with pegylated liposomal doxorubicin). Launch Date 2007

C_max

Value	Dose	Co-administered	Analyte	Population
11.3 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19417019	0.61 mg/m² 1 times / hour multiple, intravenous dose: 0.61 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TRABECTEDIN blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6.47 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19417019	0.58 mg/m² 3 times / hour multiple, intravenous dose: 0.58 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TRABECTEDIN blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
33 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19417019	0.61 mg/m² 1 times / hour multiple, intravenous dose: 0.61 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TRABECTEDIN blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
23.5 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19417019	0.58 mg/m² 3 times / hour multiple, intravenous dose: 0.58 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TRABECTEDIN blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
3% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf			TRABECTEDIN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1.5 mg/m2 1 times / 3 weeks multiple, intravenous Recommended Dose: 1.5 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 1.5 mg/m2, 1 times / 3 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf	unhealthy, 57 years (range: 17 - 81 years) n = 345 Health Status: unhealthy Age Group: 57 years (range: 17 - 81 years) Sex: M+F Population Size: 345 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf	Disc. AE: ALT increased, AST increased... AEs leading to discontinuation/dose reduction: ALT increased (5.6%) AST increased (5.6%) Alkaline phosphatase increased (5.6%) Bilirubin increased (5.6%) Thrombocytopenia (3.4%) Fatigue (1.6%) Creatine phosphokinase increased (1.1%) Ejection fraction decreased (1.1%) Elevated liver enzyme levels (24%) Neutropenia (8%) Febrile neutropenia (8%) Thrombocytopenia (4.2%) Fatigue (3.7%) Creatine phosphokinase increased (2.4%) Nausea (1.1%) Vomiting (1.1%) Neutropenia (31%) Thrombocytopenia (15%) Elevated liver enzyme levels (6%) Fatigue (2.9%) Anemia (2.6%) Creatinine increased (1.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf
1100 ug/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 1100 ug/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 1100 ug/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/15701855	unhealthy, 57 years (range: 24–77 years) n = 6 Health Status: unhealthy Condition: solid tumours Age Group: 57 years (range: 24–77 years) Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/15701855	DLT: Fatigue, Neutropenia... Other AEs: Nausea, Vomiting... Dose limiting toxicities: Fatigue (grade 3, 1 patient) Neutropenia (grade 4, 1 patient) Thrombocytopenia (grade 4, 1 patient) Other AEs: Nausea (grade 3, 50%) Vomiting (grade 3, 50%) ALT increased (grade 3-4, 4 patients) Alkaline phosphatase increased (grade 1-2, 3 patients) Hyperbilirubinaemia (grade 3-4, 1 patient) Anaemia (grade 1-2, 5 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/15701855
1800 ug/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 1800 ug/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 1800 ug/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/15701855	unhealthy, 57 years (range: 27–71 years) n = 4 Health Status: unhealthy Condition: solid tumours Age Group: 57 years (range: 27–71 years) Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/15701855	DLT: Fatigue, Thrombocytopenia... Other AEs: Nausea, Vomiting... Dose limiting toxicities: Fatigue (grade 3, 1 patient) Thrombocytopenia (grade 4, 1 patient) Bilirubinaemia (grade 3, 1 patient) Other AEs: Nausea (50%) Vomiting (grade 3-4, 50%) ALT increased (grade 3-4, 3 patients) Alkaline phosphatase increased (grade 3-4, 1 patient) Hyperbilirubinaemia (grade 3-4, 1 patient) Anaemia (grade 1-2, 4 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/15701855
1650 ug/m2 1 times / 3 weeks multiple, intravenous RP2D Dose: 1650 ug/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 1650 ug/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/15701855	unhealthy, 57 years (range: 27–71 years) n = 13 Health Status: unhealthy Condition: solid tumours Age Group: 57 years (range: 27–71 years) Sex: M+F Population Size: 13 Sources: https://pubmed.ncbi.nlm.nih.gov/15701855	DLT: Thrombocytopenia, Neutropenic infection... Other AEs: Anaemia... Dose limiting toxicities: Thrombocytopenia (grade 3, 1 patient) Neutropenic infection (grade 3, 1 patient) Other AEs: Anaemia (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/15701855

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767 inducer 389	inhibitor 1852 inducer 97

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP1A2 1524 CYP2A6 707 CYP2B6 810 CYP2C19 1478 CYP2E1 882	CYP3A 191 P-gp 1537	CYP1A2 701 CYP2A6 79 CYP2B6 547 CYP2C19 293 CYP2E1 128 CYP3A5 76

Drug as perpetrator

Target	Modality	Activity
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=24 Page: 24.0	inconclusive
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2A6 739	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2D6 1891	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2E1 970	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely
CYP3A5 130	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=53 Page: 53.0	unlikely

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=24 Page: 24.0	yes
CYP3A 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf#page=12 Page: 12.0	yes	yes (co-administration study) Comment: Coadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of YONDELIS (0.58 mg/m2 ) on day 1 increased trabectedin dose-normalized AUC by 66% and Cmax by 22% compared to a single YONDELIS dose (1.3 mg/m2 ) given alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf#page=12 Page: 12.0
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=20 Page: 20.0	yes	yes (co-administration study) Comment: Coadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of YONDELIS (0.58 mg/m2 ) on day 1 increased trabectedin dose-normalized AUC by 66% and Cmax by 22% compared to a single YONDELIS dose (1.3 mg/m2 ) given alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207953Orig1s000ClinPharmR.pdf#page=20 Page: 20.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:84050	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:84050
ChemicalBook	CB31364731	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB31364731
ZINC	ZINC000150338708	http://zinc15.docking.org/substances/ZINC000150338708

PubMed

Title	Date	PubMed
The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux.	2001 May	11329060
Pregnane X receptor-dependent and -independent effects of 2-acetylaminofluorene on cytochrome P450 3A23 expression and liver cell proliferation.	2003 Jan 10	12504080
Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766.	2006	16922593
Trabectedin : a review of its use in the management of soft tissue sarcoma and ovarian cancer.	2007	17927287
Dynamics of cell cycle phase perturbations by trabectedin (ET-743) in nucleotide excision repair (NER)-deficient and NER-proficient cells, unravelled by a novel mathematical simulation approach.	2007 Dec	18021177
A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens.	2007 Dec 17	18000504
Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development.	2009	19515014
ZNF93 increases resistance to ET-743 (Trabectedin; Yondelis) and PM00104 (Zalypsis) in human cancer cell lines.	2009 Sep 9	19742314
Disposition and toxicity of trabectedin (ET-743) in wild-type and mdr1 gene (P-gp) knock-out mice.	2010 Apr	19238326
A review of trabectedin (ET-743): a unique mechanism of action.	2010 Aug	20647340
Phase I and pharmacokinetic study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors.	2010 May 1	20406837
The activity of trabectedin as a single agent or in combination with everolimus for clear cell carcinoma of the ovary.	2011 Jul 1	21622721

Patents

Sample Use Guides

In Vivo Use Guide

Administer at 1.5 mg/m2 body surface area as a 24-hour intravenous infusion, every 3 weeks through a central venous line. Administer dexamethasone 20 mg IV, 30 min before each infusion.

Route of Administration: Intravenous

In Vitro Use Guide

Human hormone- and drug-resistant prostate cancer cell lines, PC-3 and DU145 were seeded in triplicate in 6-well plates at a density of 1×10(4) cells/well. After 24 h incubation, cells were exposed to increasing concentrations of trabectedin (0.1, 1, 10, 100 nM). Then, plates were incubated at 37C in a 5% CO2 incubator for 24, 48, and 72 h. Trabectedin reduced cell viability in all cell lines. IC50 value of trabectedin was found to be 100 nM for both cell lines after 24 and 48 h, respectively. After 48 h treatment, the IC50 values of trabectedin were found to be 10 nM, 100 nM and 9,2 nM respectively in the DU-145 cell line, DU-145 cancer stem cells (CSCs) and DU-145 non-CSCs. After 72 h treatment, the IC50 values of trabectedin were found to be 1 nM, 9.3 nM and 1 nM respectively in the DU-145 cell line, DU-145 CSCs and DU-145 non-CSCs. After 72 h treatment, the IC50 values of trabectedin were found to be 9 nM, 10 nM and 8 nM respectively in PC-3 cell line, PC-3 CSCs and PC-3 non-CSCs.

Name

Type

Language

TRABECTEDIN

Official Name

English

TRABECTEDIN [USAN]

Common Name

English

TRABECTEDIN [MART.]

Common Name

English

ET743

Code

English

ECTEINASCIDINS TRABECTEDIN [MI]

Common Name

English

TRABECTEDIN [JAN]

Common Name

English

TRABECTEDIN [EMA EPAR]

Common Name

English

ECTEINASCIDIN 743

Common Name

English

Trabectedin [WHO-DD]

Common Name

English

trabectedin [INN]

Common Name

English

NSC-648766

Code

English

TRABECTEDIN [ORANGE BOOK]

Common Name

English

ECTEINASCIDINS TRABECTEDIN

Common Name

English

ET-743

Code

English

YONDELIS

Brand Name

English

Classification Tree Code System Code

WHO-ATC

L01CX01