YM155 (Sepantronium Bromide)

YM155 (Sepantronium Bromide) is a potent survivin suppressant by inhibiting Survivin promoter activity with IC50 of 0.54 nM; does not significantly inhibit SV40 promoter activity, but is observed to slightly inhibit the interaction of Survivin with XIAP. Phase 2.

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YM155 (Sepantronium Bromide) Chemical Structure

YM155 (Sepantronium Bromide) Chemical Structure
Molecular Weight: 443.29

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Product Description

Biological Activity

Description YM155 (Sepantronium Bromide) is a potent survivin suppressant by inhibiting Survivin promoter activity with IC50 of 0.54 nM; does not significantly inhibit SV40 promoter activity, but is observed to slightly inhibit the interaction of Survivin with XIAP. Phase 2.
Targets Survivin [1]
IC50 0.54 nM
In vitro YM155 is not sensitive to survivn gene promoter-driven luciferase reporter activity even at 30 μM. YM155 significantly inhibits endogenous survivin expression in PC-3 and PPC-1 human HRPC cells with deficient p53 through transcriptional inhibition of the survivin gene promoter. On the contrary YM155 shows no sufficient effect on protein expression of c-IAP2, XIAP, Bcl-2, Bcl-xL, Bad, α-actin, and β-tubulin at 100 nM. YM155 indicates great apoptosis in human cancer cell lines including PC-3 and PPC-1 with a concomitant increase in caspase-3 activity. YM155 potently inhibits human cancer cell lines (mutated or truncated p53) including PC-3, PPC-1, DU145, TSU-Pr1, 22Rv1, SK-MEL-5 and A375 with IC50 from 2.3 to 11 nM, respectively. [1] YM155 increases the sensitivity of NSCLC cells to γ-radiation. The combination of YM155 and γ-radiation increases both the number of apoptotic cells and the activity of caspase-3. YM155 delays the repair of radiation-induced double-strand breaks in nuclear DNA. [2]
In vivo YM155 completely inhibits the tumor growth of PC-3 s.c. xenografted prostate tumors at doses of 3 and 10 mg/kg, without body weight loss and blood cell count decrease. Pharmacokinetic analysis shows that YM155 is highly distributed to tumor tissue. Moreover, YM155 shows 80% TGI at a dose of 5 mg/kg in PC-3 orthotopic xenografts. [1] The combination therapy with YM155 and γ-radiation shows great antitumor activity against H460 or Calu6 xenografts in nude mice. [2]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Promoter-luciferase reporter assay A 2,767-bp sequence of human survivin gene promoter is isolated from human genomic DNA by PCR using Pyrobest polymerase and the following primers: 5'-GCGCGCTCGAGTCTAGACATGCGGATATATTC-3' and 5'-GCGCGAA-GCTTTGGCGGTTAATGGCGCGC-3'. The resulting PCR fragment is digested with XhoI/HindIII and ligated into the XhoI/HindIII cleavage site of the pGL3-Basic vector. The resulting plasmid is named pSUR-luc. DNA sequencing is done on all amplified sequences by a DNA sequencer. The activity of pSUR-luc is confirmed by luciferase assay with transiently transfected HeLa-S3 cells. Luciferase assay is done. The pGL3 control vector, which contains the SV40 promoter and enhancer sequences, is used. HeLa cells are stably transfected with pSUR-luc and pSV2bsr by Lipofect-AMINE 2000. After blasticidin selection at 10 μg/mL, a single colony is chosen based on appropriate luciferase signals and genetic stability over time and named HeLa-SURP-luc. CHO cells are stably transfected with pGL3-control and pSV2bsr. After blasticidin selection at 10 μg/mL, a single colony is chosen based on appropriate luciferase signals and genetic stability over time and named CHO-SV40-luc. Stocked cells from the HeLa-SURP-luc and CHO-SV40-luc clones are used for chemical screening and characterization of YM155. YM155 in DMSO are added to the cells, which had been seeded the previous day on 96-well plastic plates at 5 × 103 per well. Luciferase activity is measured 24 hours later. IC50 is calculated by logistic analysis.

Cell Assay: [1]

Cell lines Hormone refractory prostate cancer cell lines (PC-3, PPC-1, DU145, TSU-Pr1 and 22Rv1) and malignant melanoma cell lines (SK-MEL-5 and A375)
Concentrations ~ 100 nM
Incubation Time 48 hours
Method Cells are seeded in 96-well plates at a density of 5-40 × 103. YM155 is dissolved in DMSO and added to cells for 48 hours. Then the cell count is determined by sulforhodamine B assay.

Animal Study: [1]

Animal Models PC-3 s.c. (orthotopic) xenografts in male nude mice (BALB/c nu/nu)
Formulation Dissolved and diluted in saline immediately before administration
Dosages 5 mg/kg
Administration Subcutaneous injection as a 3-day continuous infusion per week for 3 weeks by an implanted micro-osmotic pump
Solubility Saline, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Nakahara T, et al. Cancer Res, 2007, 67(17), 8014-8021.

[2] Iwasa T, et al. Clin Cancer Res, 2008, 14(20), 6496-6504.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-20)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01100931 Completed NSCLC|Solid Tumors National Cancer Institute (NCI)|National Institutes of He  ...more National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) February 2010 Phase 1|Phase 2
NCT01038804 Completed Breast Cancer Astellas Pharma Inc December 2009 Phase 2
NCT01023386 Completed Cancer Astellas Pharma Inc November 2009 Phase 1
NCT01007292 Active, not recruiting Non-Hodgkins Lymphoma Astellas Pharma Inc November 2009 Phase 2
NCT01009775 Completed Melanoma Astellas Pharma Inc November 2009 Phase 2

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Chemical Information

Download YM155 (Sepantronium Bromide) SDF
Molecular Weight (MW) 443.29
Formula

C20H19BrN4O3

CAS No. 781661-94-7
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 55 mg/mL (124 mM)
Water 89 mg/mL (200 mM)
Ethanol 6 mg/mL (13 mM)
In vivo Saline, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1H-Naphth[2,3-d]imidazolium, 4,9-dihydro-1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(2-pyrazinylmethyl)-, bromide (1:1)

Research Area

Customer Reviews (12)


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Rating
Source Proc Natl Acad Sci U S A 2012 109, 600-5. YM155 (Sepantronium Bromide) purchased from Selleck
Method Western blotting
Cell Lines HELF
Concentrations 0-0.5 Nm
Incubation Time 9 h
Results VZV titers decreased in the presence of YM155- compared with DMSO-treated HELF at 48 hpi (Fig. 7A ). VZV spread in YM155-treated HELF was also much more restricted compared with DMSO-treated HELF (Fig. B); mean plaque sizes were ∼0.2 mm2with YM155 compared with∼0.4 mm2with DMSO. Impaired VZV replication in the absence of survivin was furthercon firmed by decreased expression of VZV proteins IE62, ORF4, and ORF11 at 24 hpi in the presence of increasing concentrations of the survivin inhibitor (Fig. C).

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Source Leukemia 2012 26, 623-632. YM155 (Sepantronium Bromide) purchased from Selleck
Method MTS assay
Cell Lines REH/RCH/SUPB15/HAL01 cell lines
Concentrations 0-10000 nM
Incubation Time 72 h
Results Each of the cell lines tested showed a dose-dependent sensitivity to YM155 as measured by cell viability 72 h after exposure

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Source Leukemia 2012 26, 623-632. YM155 (Sepantronium Bromide) purchased from Selleck
Method Small interfering RNA knockdown
Cell Lines SUPB15 cells
Concentrations 100 nM
Incubation Time 96 h
Results Knock-down of p53 did not rescue the effects on cell viability of either imatinib or ABL siRNA. In contrast, silencing of p53 did rescue the effects of both survivin siRNA and YM155.

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Source Clin Cancer Res 2013 19, 5591-601. YM155 (Sepantronium Bromide) purchased from Selleck
Method Transwell experiments
Cell Lines U266 and UM9 cells
Concentrations 1.4 uM, 2.7 uM, 5.4 uM
Incubation Time 24 h
Results Combined YM155 with CTLs in the presence or absence of accessory cells, the CTL-mediated lysis of U266 and UM9 was markedly increased

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Source Basic Res Cardiol 2011 106, 1207-1220. YM155 (Sepantronium Bromide) purchased from Selleck
Method Cell Death Detection, ELISA, Western blot analysis
Cell Lines Neonatal rat cardiomyocytes
Concentrations 3–300 nM
Incubation Time 0-12 h
Results "As shown in Fig. a, Burn serum increased the optical density in neonatal rat cardiomyocytes from 0.21 ± 0.01 to 1.10 ± 0.11. YM155 could further enhanced burn serum-induced apoptosis in a concentration-dependent manner, with a significant cell apoptosis effect detectable at 100 nM, and a more pronounced effect at 300 nM. Therefore, in all subsequent experiments in vitro, we used 100 nM YM155 to inhibit survivin expression. From Fig. b, the apoptosis induced by burn serum was increased by YM155, not only at 2 h, but also at 12 h. Furthermore, when cardiomyocytes were pre-incubated with YM155 2 h prior burn serum stimulation, the levels of cleaved caspase-3 were significantly greater than those from cells pretreated with vehicle (Fig. c, middle panel, and d, right panel).

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Source Basic Res Cardiol 2011 106, 1207-1220. YM155 (Sepantronium Bromide) purchased from Selleck
Method Western blot analysis, TUNEL assay, Immunostaining for survivin protein
Cell Lines Neonatal rat cardiomyocytes
Concentrations 5 mg/kg/day
Incubation Time 5 d
Results After the animals were pretreated with YM155 (5 mg/kg/day) for 5 days, the level of survivin decreased to 80, 78 and 52% of the baseline expression in non-injury, sham burn or burn injury hearts (Fig. a, top panel, and b, left panel). The basal cleaved caspase-3 level was almost undetectable, whereas after injection of YM155 for 5 days, the expression was significantly elevated to 6.5-fold (Fig. a, middle panel, and b, right panel). After 6 h of burn injury, the level of cleaved caspase-3 increased to 9.0-fold. Furthermore, in the normal or sham rats, there were no apoptotic staining in the hearts examined (Fig. c). When animals were pretreated with YM155, the apoptotic staining was significantly increased, particularly after the burn (0.61 ± 0.25% in normal group, 0.72 ± 0.17% in sham group, 2.18 ± 0.43% in YM155 group) (Fig. d), suggesting that the survivin is an important anti-apoptotic regulator of cardiomyocytes after burn injury.

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Source PLoS One 2011 6, e21980. YM155 (Sepantronium Bromide) purchased from Selleck
Method Hoechst staining, Western blotting, Cell colony formation assays
Cell Lines LH86 cells, Huh7 cells
Concentrations 1 µM
Incubation Time 6 h
Results As shown in Figure A, B, C, D, E and F, neither ABT-263(1 µM) nor YM-155(1 µM) single treatment was able to induce apoptotic events in HCC cells. Surprisingly, a combination treatment of ABT-263 (1 µM) with YM-155 (1 µM) induced dramatic apoptosis within 6 h. Additional experiments were done to determine the anti-tumor activities of combination of ABT-263 and YM-155 inhibition when analyzed by in vitro colony formation assays. As shown in Figure G and F, median dose of ABT-263 and YM-155 combination treatment significantly reduced HCC cell proliferation. These results suggest that survivin inhibitor YM-155 can sensitize ABT-263 to induce apoptosis in HCC cells.

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Source PLoS One 2011 6, e21980. YM155 (Sepantronium Bromide) purchased from Selleck
Method Western blotting, Hoechst staining
Cell Lines LH86 cells
Concentrations 1 µM
Incubation Time 6 h
Results As shown in Figure A, the combination treatment of HCC cells with ABT-263 (1 µM) and YM-155 (1 µM) for up to 6 h has no effects on the expressions of either anti-apoptotic protein Bcl-xL or pro-apoptotic proteins including Bad, Bak, and Bax. However, as expected, the presence of YM-155 significantly decreased survivin protein expression (Figure B, left third lane). Co-treatment of cells with ABT-263 (1 µM) and YM-155 (1 µM) induced an even greater decrease in survivin protein expression (Figure B, right two lanes) than that of YM-155 itself did. However, we indeed observed that ABT-263 single treatment for 3 h resulted in survivin increase (Figure B). To further determine survivin inhibition plays a critical role in sensitizing ABT-263 to induce apoptosis in HCC cells, we down-regulated survivin expression in HCC cells by siRNA duplexes targeted against human survivin mRNA, and then examined the expression of survivin by Western blotting (Figure C) and apoptotic events after ABT-263 treatments. The results demonstrated that ABT-263 induced significant apoptosis in the survivin siRNA-transfected cells, but not in siRNA Random-transfected (control) cells (Figure D, E, and F).

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Source Anticancer Res 2012 32, 1681-8. YM155 (Sepantronium Bromide) purchased from Selleck
Method Immunoblot analysis/Cell cycle analysis/cytotoxicity assay
Cell Lines MiaPaCa2 cell line
Concentrations 2-16 nM
Incubation Time
Results YM155 induced cell death in a dose-dependent manner(Figure A); however, marked cell cycle arrest was not noted, merely an increased proportion of cells in the subG1 fraction. and a decrease in the G1 fraction (Figure B). YM155 treatment successfully suppressed the mRNA and the protein expression of survivin, as confirmed by RT-PCR and westernblot analysis (Figure C and D). In addition, the cleavage of PARP increased in accordance with the increase in the proportion of dead cells induced by YM155 (Figure D).

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Source Adv Biosci Biotechnol 2012 3, 657-664. YM155 (Sepantronium Bromide) purchased from Selleck
Method Apoptosis assay
Cell Lines IPF fibroblasts
Concentrations 10 µM
Incubation Time 16 h
Results There was strong correlation between apoptosis induced by Fas-activation with YM155 and Fas-activation with CAY1062.

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Source Lihua Min of Chinese Academy of Sciences. YM155 (Sepantronium Bromide) purchased from Selleck
Method qRT-PCR
Cell Lines liver cell
Concentrations
Incubation Time 48 h
Results Total RNA from livers of these mice were isolated from tissues using TRIZOL (Invitrogen). cDNA synthesis was performed with the M-MLV RTase cDNA Synthesis Kit (Promega). qRT-PCR reactions were performed using SYBR Green (Takara) on ABI 7500 Fast system. Expression levels of Survivin gene were measured by qRT-PCR in livers injected with 0.9% Nacl (91#,92#) or YM155 48 hours after DEN treatment.

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Source Dr. Chunrong Yu of RoswelI Park Cancer Institute. YM155 (Sepantronium Bromide) purchased from Selleck
Method Western blotting
Cell Lines U-251 cell line, PC-3 cell line
Concentrations 0-100 nM
Incubation Time
Results

Product Citations (23)

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