SEPANTRONIUM BROMIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H19N4O3.Br
Molecular Weight	443.294
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Br-].COCC[N+]1=C(C)N(CC2=NC=CN=C2)C3=C1C(=O)C4=CC=CC=C4C3=O

InChI

InChIKey=QBIYUDDJPRGKNJ-UHFFFAOYSA-M

InChI=1S/C20H19N4O3.BrH/c1-13-23(9-10-27-2)17-18(24(13)12-14-11-21-7-8-22-14)20(26)16-6-4-3-5-15(16)19(17)25;/h3-8,11H,9-10,12H2,1-2H3;1H/q+1;/p-1

HIDE SMILES / InChI

Molecular Formula	C20H19N4O3
Molecular Weight	363.3899
Charge	1
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	BrH
Molecular Weight	80.912
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26018732 | http://en.pharmacodia.com/yaodu/html/v1/chemicals/26f6abfa0d7725fef678e371897d5df0.html

Sepantronium bromide (YM155) is a selective survivin suppressant that exhibits potent antitumor activities by inducing apoptosis and autophagy in various types of cancer. Sepantronium bromide inhibited the growth of various human cancer cell lines in vitro with GI50 values in the low nM range. Sepantronium bromide blocked the growth of 119 human cancer cell lines, with the greatest inhibition in lines derived from non-Hodgkin's lymphoma, hormone-refractory prostate cancer, ovarian cancer, sarcoma, non-small-cell lung cancer, breast cancer, leukemia, and melanoma, with an average GI50 of 15 nM. Sepantronium bromide inhibited the growth of tumor cell lines regardless of their p53 status and demonstrated significant antitumor activity in 5 mice xenograft models. It also caused tumor regressions in vivo, possibly by its effects in reducing intratumoral survivin expression levels and increasing apoptosis. Sepantronium Bromide had been in phase II clinical trials by Astellas for the treatment of prostate cancer, melanoma, non-Hodgkin's lymphoma, breast cancer, diffuse large B cell lymphoma, non-small cell lung cancer (NSCLC) and other solid tumors. This compound had also been in clinical trials by National Cancer Institute (NCI) for the treatment of solid tumors (phase I) and advanced non-small cell lung cancer (NSCLC) (phase II). However, all these researches about this compound for all indications were discontinued.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Baculoviral IAP repeat-containing protein 5 3 Target ID: CHEMBL5989 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26090615 \| https://www.ncbi.nlm.nih.gov/pubmed/17804712	Inhibitor 8297		0.54 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-Hodgkin's lymphoma 79 Sources: https://clinicaltrials.gov/ct2/show/NCT00818480 http://adisinsight.springer.com/drugs/800023625	Primary	Phase II 1132	Unknown Approved Use Unknown
Prostate cancer 178 Sources: https://clinicaltrials.gov/ct2/show/NCT00818480 http://adisinsight.springer.com/drugs/800023625	Primary	Phase II 1132	Unknown Approved Use Unknown
Melanoma 88 Sources: https://clinicaltrials.gov/ct2/show/NCT00818480 http://adisinsight.springer.com/drugs/800023625	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT01100931 http://adisinsight.springer.com/drugs/800023625	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
10.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18824702	4.8 mg/m² 1 times / day steady-state, intravenous dose: 4.8 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		SEPANTRONIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1439 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18824702	4.8 mg/m² 1 times / day steady-state, intravenous dose: 4.8 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		SEPANTRONIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
26.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18824702	4.8 mg/m² 1 times / day steady-state, intravenous dose: 4.8 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		SEPANTRONIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
10.6 mg/m2/day 1 times / day steady-state, intravenous Highest studied dose Dose: 10.6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 10.6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874	unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874	DLT: Serum creatinine increased... Other AEs: Lymphocytopenia, Lymphocytopenia... Dose limiting toxicities: Serum creatinine increased (40%) Other AEs: Lymphocytopenia (grade 4, 20%) Lymphocytopenia (grade 3-4, 80%) Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874
4.8 mg/m2/day 1 times / day steady-state, intravenous MTD Dose: 4.8 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 4.8 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	unhealthy, ADULT n = 25 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 25 Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	DLT: Febrile neutropenia, Stomatitis... Dose limiting toxicities: Febrile neutropenia (grade 4, 4%) Stomatitis (grade 3, 4%) Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200
8 mg/m2/day 1 times / day steady-state, intravenous MTD Dose: 8 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 8 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874	Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874
6 mg/m2/day 1 times / day steady-state, intravenous Studied dose Dose: 6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	DLT: Neutropenia, Stomatitis... Disc. AE: Acute tubular necrosis... Dose limiting toxicities: Neutropenia (grade 4, 50%) Stomatitis (grade 2-3, 100%) Serum creatinine increased (100%) AEs leading to discontinuation/dose reduction: Acute tubular necrosis (50%) Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200

AEs

AE	Significance	Dose	Population
Serum creatinine increased	40% DLT	10.6 mg/m2/day 1 times / day steady-state, intravenous Highest studied dose Dose: 10.6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 10.6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874	unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874
Lymphocytopenia	grade 3-4, 80%	10.6 mg/m2/day 1 times / day steady-state, intravenous Highest studied dose Dose: 10.6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 10.6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874	unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874
Lymphocytopenia	grade 4, 20%	10.6 mg/m2/day 1 times / day steady-state, intravenous Highest studied dose Dose: 10.6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 10.6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874	unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19470738 Page: p.3874
Stomatitis	grade 3, 4% DLT	4.8 mg/m2/day 1 times / day steady-state, intravenous MTD Dose: 4.8 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 4.8 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	unhealthy, ADULT n = 25 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 25 Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200
Febrile neutropenia	grade 4, 4% DLT	4.8 mg/m2/day 1 times / day steady-state, intravenous MTD Dose: 4.8 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 4.8 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	unhealthy, ADULT n = 25 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 25 Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200
Serum creatinine increased	100% DLT, Disc. AE	6 mg/m2/day 1 times / day steady-state, intravenous Studied dose Dose: 6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200
Acute tubular necrosis	50% Disc. AE	6 mg/m2/day 1 times / day steady-state, intravenous Studied dose Dose: 6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200
Stomatitis	grade 2-3, 100% DLT, Disc. AE	6 mg/m2/day 1 times / day steady-state, intravenous Studied dose Dose: 6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200
Neutropenia	grade 4, 50% DLT, Disc. AE	6 mg/m2/day 1 times / day steady-state, intravenous Studied dose Dose: 6 mg/m2/day, 1 times / day Route: intravenous Route: steady-state Dose: 6 mg/m2/day, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/18824702 Page: p.5200

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT1 512 P-gp 1461 OCT2 647 OCT3 150	OATP2B1 104 P-gp 1537 OCTN2 50 OCT2 355 OAT1 326 OCT3 80 OAT3 339 MRP2 205 OCT1 327 MPR3 2 BCRP 561 MRP1 107 OATP1B1 406 OCTN1 47 OATP1B3 350

Drug as perpetrator

Target	Modality	Activity
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=124950713	inconclusive [IC50 16.6261 uM]
OCT3 150	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19833842/	weak [IC50 108 uM]
OCT2 648	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19833842/	yes [IC50 15.9 uM]
OCT1 543	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19833842/	yes [IC50 23.8 uM]

Drug as victim

Target	Modality	Activity
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21918035/	no
MPR3 2	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21918035/	no
OAT1 326	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22806304/	no
OAT3 339	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22806304/	no
OATP1B1 406	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22806304/	no
OATP1B3 350	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22806304/	no
OATP2B1 104	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22806304/	no
OCT3 80	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19833842/	no
OCTN1 47	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22806304/	no
OCTN2 50	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22806304/	no
MRP1 107	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21918035/	weak
MRP2 205	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21918035/	weak
OCT2 355	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19833842/	yes [Km 2.67 uM]
OCT1 327	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19833842/ \| https://pubmed.ncbi.nlm.nih.gov/22806304/	yes [Km 22.1 uM]
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21918035/	yes

PubMed

Title	Date	PubMed
YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts.	2007 Sep 1	17804712
Combination of YM155, a survivin suppressant with a STAT3 inhibitor: a new strategy to treat diffuse large B-cell lymphoma.	2013 Sep	23746965
Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells.	2014 Feb	24297644
Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma.	2015 May 28	26018732

Patents

Sample Use Guides

In Vivo Use Guide

Solid tumors treatment: Phase I: Doses were given at different dose levels until the maximum tolerated dose (MTD) was reached. Dose level 1: 3.6 mg/m^2, dose level 2:5 mg/m^2 , dose level 3:6 mg/m^2, dose level 4:8 mg/m^2, dose level 5:10 mg/m^2 (MTD), dose level 6:12 mg/m^2. Doses were given by continuous intravenous infusion over 72 hours every 21 days.Three patients were enrolled at each dose level in the absence of dose limiting toxicity (DLT). A DLT is defined as adverse events occurring during the first cycle of therapy (e.g. every 21 days). Phase II: 10 mg/m^2 (MTD)intravenous infusion over 72 hours every 21 days.

Route of Administration: Intravenous

In Vitro Use Guide

Sepantronium bromide (YM155) suppressed the expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2-related proteins.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 16:00:26 UTC 2023` Edited by `admin` on `Sat Dec 16 16:00:26 UTC 2023`
Record UNII	7H5Q4J1CM5
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

SEPANTRONIUM BROMIDE

Official Name

English

Sepantronium bromide [WHO-DD]

Common Name

English

SEPANTRONIUM BROMIDE [USAN]

Common Name

English

SEPANTRONIUM BROMIDE [JAN]

Common Name

English

YM155

Code

English

YM-155

Code

English

1H-NAPHTH(2,3-D)IMIDAZOLIUM, 4,9-DIHYDRO-1-(2-METHOXYETHYL)-2-METHYL-4,9-DIOXO-3-(2-PYRAZINYLMETHYL)-, BROMIDE (1:1)

Systematic Name

English

sepantronium bromide [INN]

Common Name

English

1-(2-METHOXYETHYL)-2-METHYL-4,9-DIOXO-3-((PYRAZIN-2-YL)METHYL)-4,9-DIHYDRO-1H-NAPHTHO(2,3-D)IMIDAZOLIUM BROMIDE

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2189