Lurbinectedin

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C41H44N4O10S
Molecular Weight	784.874
Optical Activity	UNSPECIFIED
Defined Stereocenters	7 / 7
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[H][C@@]12[C@@H]3SC[C@]4(NCCC5=C4NC6=C5C=C(OC)C=C6)C(=O)OC[C@H](N1[C@@H](O)[C@@H]7CC8=CC(C)=C(OC)C(O)=C8[C@H]2N7C)C9=C%10OCOC%10=C(C)C(OC(C)=O)=C39

InChI

InChIKey=YDDMIZRDDREKEP-HWTBNCOESA-N

InChI=1S/C41H44N4O10S/c1-17-11-20-12-25-39(48)45-26-14-52-40(49)41(38-22(9-10-42-41)23-13-21(50-5)7-8-24(23)43-38)15-56-37(31(45)30(44(25)4)27(20)32(47)33(17)51-6)29-28(26)36-35(53-16-54-36)18(2)34(29)55-19(3)46/h7-8,11,13,25-26,30-31,37,39,42-43,47-48H,9-10,12,14-16H2,1-6H3/t25-,26-,30+,31+,37+,39-,41+/m0/s1

HIDE SMILES / InChI

Molecular Formula	C41H44N4O10S
Molecular Weight	784.874
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	7 / 7
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Lurbinectedin (PM-01183) - is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity. Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death. Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
RNA Polymerase II Transcription 1	Inhibitor 8,504

Conditions

Condition	Modality	Targets	Highest Phase	Product
Ovarian cancer 160	Primary		Phase III 665	Unknown
Non-small cell lung cancer 211	Primary		Phase III 665	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
153.8 ng/mL	7 mg 1 times / 3 weeks multiple, intravenous		LURBINECTEDIN plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
532.6 ng × h/mL	7 mg 1 times / 3 weeks multiple, intravenous		LURBINECTEDIN plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
51.4 h	7 mg 1 times / 3 weeks multiple, intravenous		LURBINECTEDIN plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
3.2 mg/m2 1 times / 3 weeks steady, intravenous Recommended	unhealthy, 60 years (range: 40 - 83 years)	Disc. AE: Peripheral neuropathy, Myelosuppression...
6.9 mg/m2 1 times / 3 weeks steady, intravenous Highest studied dose	unhealthy
4 mg/m2 1 times / 3 weeks steady, intravenous MTD	unhealthy	DLT: Thrombocytopenia...
5 mg/m2 1 times / 3 weeks steady, intravenous Studied dose	unhealthy	DLT: AST increased, Neutropenia...

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AEs

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AE	Significance	Dose	Population
Myelosuppression	>1 Disc. AE	3.2 mg/m2 1 times / 3 weeks steady, intravenous Recommended	unhealthy, 60 years (range: 40 - 83 years)
Peripheral neuropathy	>1 Disc. AE	3.2 mg/m2 1 times / 3 weeks steady, intravenous Recommended	unhealthy, 60 years (range: 40 - 83 years)
Fatigue	>3 Disc. AE	3.2 mg/m2 1 times / 3 weeks steady, intravenous Recommended	unhealthy, 60 years (range: 40 - 83 years)
Febrile neutropenia	>3 Disc. AE	3.2 mg/m2 1 times / 3 weeks steady, intravenous Recommended	unhealthy, 60 years (range: 40 - 83 years)
Hypoalbuminemia	>3 Disc. AE	3.2 mg/m2 1 times / 3 weeks steady, intravenous Recommended	unhealthy, 60 years (range: 40 - 83 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946 inhibitor 2,252 inducer 1,087	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,741 OATP1B1 1,079 OATP1B3 961 OCT1 620 CYP1A2 2,153 CYP2B6 926 CYP2C8 1,057 CYP2C19 2,057 CYP2E1 1,060	P-gp 2,052 OATP1B3 435 OCT1 393 MATE1 182 BCRP 697 BSEP 63 OAT1 395 OAT3 391 OCT2 434	CYP1A2 832

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 2,333	inducer 1,966	no
CYP1A2 2,333	inhibitor 4,027	no
CYP2B6 1,160	inhibitor 4,027	no
CYP2C19 2,141	inhibitor 4,027	no
CYP2C8 1,117	inhibitor 4,027	no

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Drug as victim

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Target	Modality	Activity
CYP3A4 1,946	substrate 4,014	major
BCRP 697	substrate 4,014	no
BSEP 63	substrate 4,014	no
MATE1 182	substrate 4,014	no
OAT1 395	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA00DJWD	https://www.aablocks.com/goods/Goods/detail?id=AA00DJWD
AbMole Bioscience	M10037	http://www.abmole.com/products/lurbinectedin.html
BLD Pharm	BD00825727	http://www.bldpharm.com/products/497871-47-3.html
Chem Scene	CS-6323	http://www.chemscene.com/497871-47-3.html
Chemspace	CSSS00161189527	https://chem-space.com/CSSS00161189527

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PubMed

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Title	Date	PubMed
Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models.	2017 Aug 22	28683469
Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer.	2017 Jun 1	28368437

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Patents

Sample Use Guides

In Vivo Use Guide

Non-Small Cell Lung Cancer: 3.2 mg/m2 Lurbinectedin (PM01183), day 1, 1-hour intravenous, every three weeks

Route of Administration: Intravenous

In Vitro Use Guide

48 hours’ treatment with lurbinectedin (0.3–10 nmol/L) inhibited the proliferation of the ovarian cancer cells of CCC origin in a dose-dependent manner.

Substance Class	Chemical
Record UNII	2CN60TN6ZS
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

PM-01183

Preferred Name

English

Lurbinectedin

Official Name

English

LURBINECTEDIN [MI]

Common Name

English

PM1183

Code

English

LURBINECTEDIN [USAN]

Common Name

English

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Classification Tree

Code System

Code

DNA Binding Agent

NCI_THESAURUS

C25760

Positive

EU-Orphan Drug

EU/3/19/2143

Designated/Approved

FDA ORPHAN DRUG

646018

DNA Groove Binding Agent

NCI_THESAURUS

C2115

Designated

FDA ORPHAN DRUG

376512

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Code System

Code

Type

Description

EPA CompTox

DTXSID30198065

PRIMARY

DRUG BANK

DB12674

PRIMARY

WIKIPEDIA

Lurbinectedin

PRIMARY

NCI_THESAURUS

C82382

PRIMARY

INN

9397

PRIMARY

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Related Record

Type

Details


					2CN60TN6ZS

Lurbinectedin

EXCRETED UNCHANGED

Qualification:

FECAL

Amount:

[<0.2] % (average)


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE


					ONY583280Z

OCT-1

TRANSPORTER -> INHIBITOR


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> INHIBITOR

Amount:


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> SUBSTRATE

Amount:

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Related Record

Type

Details


					SPI9H51GW7

LURBINECTEDIN METABOLITE M1

METABOLITE -> PARENT

Interaction Type:

MAJOR

Qualification:

FECAL; PLASMA; URINE

Amount:

14 % (average)
of parent drug


					CGD1PI0B4S

PM-030047

METABOLITE -> PARENT

Interaction Type:

MAJOR

Qualification:

FECAL; PLASMA; URINE

Amount:

10 % (average)
of parent drug

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Related Record

Type

Details


					2CN60TN6ZS

Lurbinectedin

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
Biological Half-life	PHARMACOKINETIC	51 hours (average)

Volume of Distribution	PHARMACOKINETIC	504 LITERS (average)	AT STEADY-STATE

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator