Sepantronium bromide
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MedKoo CAT#: 203190

CAS#: 781661-94-7

Description: Sepantronium bromide, also known as YM-155, is a small-molecule proapoptotic agent with potential antineoplastic activity. Survivin inhibitor YM155 selectively inhibits survivin expression in tumor cells, resulting in inhibition of survivin antiapoptotic activity (via the extrinsic or intrinsic apoptotic pathways) and tumor cell apoptosis. Survivin, a member of the inhibitor of apoptosis (IAP) gene family, is expressed during embryonal development and is absent in most normal, terminally differentiated tissues; upregulated in a variety of human cancers, its expression in tumors is associated with a more aggressive phenotype, shorter survival times, and a decreased response to chemotherapy.


Chemical Structure

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Sepantronium bromide
CAS# 781661-94-7

Theoretical Analysis

MedKoo Cat#: 203190
Name: Sepantronium bromide
CAS#: 781661-94-7
Chemical Formula: C20H19BrN4O3
Exact Mass:
Molecular Weight: 443.29
Elemental Analysis: C, 54.19; H, 4.32; Br, 18.03; N, 12.64; O, 10.83

Price and Availability

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100.0mg USD 450.0 Ready to ship
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500.0mg USD 1550.0 Ready to ship
1.0g USD 2550.0 Ready to ship
2.0g USD 4350.0 2 Weeks
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Synonym: YM155; YM 155; YM-155; Sepantronium bromide

IUPAC/Chemical Name: 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide.

InChi Key: QBIYUDDJPRGKNJ-UHFFFAOYSA-M

InChi Code: 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

SMILES Code: O=C(C1=C2[N+](CCOC)=C(C)N1CC3=NC=CN=C3)C4=C(C=CC=C4)C2=O.[Br-]

Appearance: White Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Sepantronium bromide (YM-155) is a survivin inhibitor with an IC50 of 0.54 nM.
In vitro activity: To identify a novel small molecule that specifically inhibits survivin expression in human cancer cells, a high-throughput screening of in-house chemical compound libraries using the transformants stably expressing survivin gene promoter–driven luciferase reporter or SV40 enhancer/promoter–driven luciferase reporter was conducted. YM155 was identified as a novel small-molecule survivin gene suppressant ( Table 1 ). YM155 potently inhibited survivin promoter activity with an IC50 value of 0.54 nmol/L but did not significantly inhibit SV40 promoter activity at concentrations up to 30 μmol/L. The in vitro effect of YM155 was further confirmed on endogenous survivin expression in PC-3 and PPC-1 human HRPC cells with deficient p53 ( Fig. 1A–C ). YM155 administered from 10 to 1,000 nmol/L significantly suppressed survivin expression in a dose-dependent manner ( Fig. 1A), as observed at 6 h after the drug addition ( Fig. 1B). These results clearly show that at similar time points, YM155 suppresses survivin at the mRNA and protein levels, which suggests that the suppression of survivin by YM155 is through transcriptional inhibition of the survivin gene promoter. Reference: Cancer Res. 2012 Aug 1;72(15):3886. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17804712
In vivo activity: The in vivo antitumor activity of YM155 was evaluated in PC-3 orthotopic xenografts, a more clinically relevant model of HRPC ( Fig. 5 ). YM155 administered at 1 and 5 mg/kg showed 47% and 80% inhibition of tumor growth, respectively, compared with controls ( Fig. 5A). For this evaluation, because the excised prostate and seminal vesicles were both included in the tumor weight, YM155 treatment almost completely inhibited tumor growth ( Fig. 5C). After orthotopic implantation of PC-3, control mice showed a marked decrease in body weight and a deterioration of general health as the tumors progressed ( Fig. 5B). Mice treated with YM155, however, showed improved general health and body weight gain. These results strongly suggest that YM155 may potentially show clinical benefits in patients with HRPC. Reference: Cancer Res. 2012 Aug 1;72(15):3886. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17804712

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 55.0 124.07
Water 89.0 200.77

Preparing Stock Solutions

The following data is based on the product molecular weight 443.29 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Hatakeyama S, Kinoyama I, Matsuhisa A, Kudoh M, Sasamata M. YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res. 2007 Sep 1;67(17):8014-21. doi: 10.1158/0008-5472.CAN-07-1343. Erratum in: Cancer Res. 2012 Aug 1;72(15):3886. Mori, Masamichi [added]; Amino, Nobuaki [added]; Hatakeyama, Shinji [added];Minematsu, Tsuyoshi [removed]; Shirasuna, Kenna[removed]. PMID: 17804712. 2. Iwasa T, Okamoto I, Suzuki M, Nakahara T, Yamanaka K, Hatashita E, Yamada Y, Fukuoka M, Ono K, Nakagawa K. Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines. Clin Cancer Res. 2008 Oct 15;14(20):6496-504. doi: 10.1158/1078-0432.CCR-08-0468. PMID: 18927289.
In vivo protocol: 1. Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Hatakeyama S, Kinoyama I, Matsuhisa A, Kudoh M, Sasamata M. YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res. 2007 Sep 1;67(17):8014-21. doi: 10.1158/0008-5472.CAN-07-1343. Erratum in: Cancer Res. 2012 Aug 1;72(15):3886. Mori, Masamichi [added]; Amino, Nobuaki [added]; Hatakeyama, Shinji [added];Minematsu, Tsuyoshi [removed]; Shirasuna, Kenna[removed]. PMID: 17804712.

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1: Hong M, Ren MQ, Silva J, Paul A, Wilson WD, Schroeder C, Weinberger P, Janik J, Hao Z. YM155 inhibits topoisomerase function. Anticancer Drugs. 2016 Oct 13. PubMed PMID: 27754993.

2: Voges Y, Michaelis M, Rothweiler F, Schaller T, Schneider C, Politt K, Mernberger M, Nist A, Stiewe T, Wass MN, Rödel F, Cinatl J. Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance. Cell Death Dis. 2016 Oct 13;7(10):e2410. doi: 10.1038/cddis.2016.257. PubMed PMID: 27735941.

3: Zhang S, Wang X, Gu Z, Wang L. Small Molecule Survivin Inhibitor YM155 Displays Potent Activity Against Human Osteosarcoma Cells. Cancer Invest. 2016 Sep 13;34(8):401-7. doi: 10.1080/07357907.2016.1212205. Epub 2016 Aug 25. PubMed PMID: 27559851.

4: Woo SM, Min KJ, Seo BR, Kwon TK. YM155 sensitizes TRAIL-induced apoptosis through cathepsin S-dependent down-regulation of Mcl-1 and NF-κB-mediated down-regulation of c-FLIP expression in human renal carcinoma Caki cells. Oncotarget. 2016 Aug 9. doi: 10.18632/oncotarget.11137. [Epub ahead of print] PubMed PMID: 27528031.

5: Zhang W, Liu Y, Li YF, Yue Y, Yang X, Peng L. Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells. Cell Physiol Biochem. 2016;38(6):2426-37. doi: 10.1159/000445594. Epub 2016 Jun 13. PubMed PMID: 27287458.

6: Gyurászová K, Mikeš J, Halaburková A, Jendželovský R, Fedoročko P. YM155, a small molecule inhibitor of survivin expression, sensitizes cancer cells to hypericin-mediated photodynamic therapy. Photochem Photobiol Sci. 2016 Jun 8;15(6):812-21. doi: 10.1039/c5pp00438a. Epub 2016 May 31. PubMed PMID: 27241169.

7: Zhang J, Xu R, Tao X, Dong Y, Lv X, Sun A, Wei D. TAT-IL-24-KDEL-induced apoptosis is inhibited by survivin but restored by the small molecular survivin inhibitor, YM155, in cancer cells. Oncotarget. 2016 Jun 14;7(24):37030-37042. doi: 10.18632/oncotarget.9458. PubMed PMID: 27203744.

8: de Haart SJ, Holthof L, Noort WA, Minnema MC, Emmelot ME, Aarts-Riemens T, Doshi P, Sasser K, Yuan H, de Bruijn J, Martens AC, van de Donk NW, Lokhorst HM, Groen RW, Mutis T. Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance. Haematologica. 2016 Aug;101(8):e339-42. doi: 10.3324/haematol.2015.139667. Epub 2016 May 5. PubMed PMID: 27151995; PubMed Central PMCID: PMC4967585.

9: Ueno T, Uehara S, Nakahata K, Okuyama H. Survivin selective inhibitor YM155 promotes cisplatin induced apoptosis in embryonal rhabdomyosarcoma. Int J Oncol. 2016 May;48(5):1847-54. doi: 10.3892/ijo.2016.3438. Epub 2016 Mar 10. PubMed PMID: 26983495.

10: Zhang S, Liu B, Fan Z, Wang D, Liu Y, Li J, Wang N, Liu Y, Zhang B. Targeted inhibition of survivin with YM155 promotes apoptosis of hypoxic human pulmonary arterial smooth muscle cells via the upregulation of voltage-dependent K⁺ channels. Mol Med Rep. 2016 Apr;13(4):3415-22. doi: 10.3892/mmr.2016.4977. Epub 2016 Mar 4. PubMed PMID: 26957114; PubMed Central PMCID: PMC4805101.

11: Ho SH, Ali A, Chin TM, Go ML. Dioxonaphthoimidazoliums AB1 and YM155 disrupt phosphorylation of p50 in the NF-κB pathway. Oncotarget. 2016 Mar 8;7(10):11625-36. doi: 10.18632/oncotarget.7299. PubMed PMID: 26872379; PubMed Central PMCID: PMC4905498.

12: Papadopoulos KP, Lopez-Jimenez J, Smith SE, Steinberg J, Keating A, Sasse C, Jie F, Thyss A. A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma. Leuk Lymphoma. 2016 Aug;57(8):1848-55. doi: 10.3109/10428194.2015.1113275. Epub 2016 Feb 9. PubMed PMID: 26857688.

13: Li WL, Lee MR, Cho MY. The small molecule survivin inhibitor YM155 may be an effective treatment modality for colon cancer through increasing apoptosis. Biochem Biophys Res Commun. 2016 Mar 4;471(2):309-14. doi: 10.1016/j.bbrc.2016.02.009. Epub 2016 Feb 15. PubMed PMID: 26855135.

14: Cheng XJ, Lin JC, Ding YF, Zhu L, Ye J, Tu SP. Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues. Oncotarget. 2016 Feb 9;7(6):7096-109. doi: 10.18632/oncotarget.6898. PubMed PMID: 26771139; PubMed Central PMCID: PMC4872771.

15: Zhang Z, Zhang Y, Lv J, Wang J. The survivin suppressant YM155 reverses doxorubicin resistance in osteosarcoma. Int J Clin Exp Med. 2015 Oct 15;8(10):18032-40. eCollection 2015. PubMed PMID: 26770398; PubMed Central PMCID: PMC4694298.

16: Zhang C, Cao X, Gei Y, Wang Y, Liu G, Cheng G, Liu Q. Silencing of survivin by YM155 induces apoptosis and growth arrest in hepatocellular carcinoma cells. Oncol Lett. 2015 Sep;10(3):1627-1631. Epub 2015 Jul 2. PubMed PMID: 26622722; PubMed Central PMCID: PMC4533751.

17: Sasaki R, Ito S, Asahi M, Ishida Y. YM155 suppresses cell proliferation and induces cell death in human adult T-cell leukemia/lymphoma cells. Leuk Res. 2015 Dec;39(12):1473-9. doi: 10.1016/j.leukres.2015.10.012. Epub 2015 Oct 27. PubMed PMID: 26547260.

18: Ho SH, Sim MY, Yee WL, Yang T, Yuen SP, Go ML. Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure-activity relationship study. Eur J Med Chem. 2015 Nov 2;104:42-56. doi: 10.1016/j.ejmech.2015.09.026. Epub 2015 Sep 25. PubMed PMID: 26433618.

19: Hu S, Fu S, Xu X, Chen L, Xu J, Li B, Qu Y, Yu H, Lu S, Li W. The mechanism of radiosensitization by YM155, a novel small molecule inhibitor of survivin expression, is associated with DNA damage repair. Cell Physiol Biochem. 2015;37(3):1219-30. doi: 10.1159/000430245. Epub 2015 Sep 30. PubMed PMID: 26418254.

20: Minoda M, Kawamoto T, Ueha T, Kamata E, Morishita M, Harada R, Toda M, Onishi Y, Hara H, Kurosaka M, Akisue T. Antitumor effect of YM155, a novel small-molecule survivin suppressant, via mitochondrial apoptosis in human MFH/UPS. Int J Oncol. 2015 Sep;47(3):891-9. doi: 10.3892/ijo.2015.3077. Epub 2015 Jul 9. PubMed PMID: 26166250; PubMed Central PMCID: PMC4532197.



Additional Information

Phase II trials: To evaluate the antitumor activity and safety of YM155, a novel, small-molecule suppressor of survivin, as single-agent therapy in patients with previously treated, advanced non-small-cell lung cancer (NSCLC). RESULTS: Thirty-seven patients received YM155. Two patients achieved a confirmed partial response, with an ORR of 5.4% (95% CI, 0.7% to 18.2%). An additional 14 patients (37.8%) achieved SD resulting in a disease control rate of 43.2% (95% CI, 27.1% to 60.5%). Median duration of PFS was 1.7 months (95% CI, 1.3 to 2.8 months). Median duration of OS was 6.6 months (95% CI, 4 to 12.2 months), with a 1-year survival rate of 35.1%. Treatment with YM155 was well tolerated with the majority of treatment discontinuations not treatment related. CONCLUSION: YM155 exhibited modest single-agent activity in patients with refractory, advanced NSCLC. A favorable safety/tolerability profile was reported. Further evaluation of YM155 in combination with chemotherapy and other targeted agents may be warranted.
  
 
 
Highlight on most recent research using YM-155
Highlight on most recent research using YM-155
 
 
Data published in June 2011
Data published in June 2011
YM155 enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model. Survivin, an apoptotic inhibitor, is overexpressed in the majority of human tumor types and represents a novel target for anticancer therapy. Taxanes induce a mitotic cell-cycle block through the inhibition of microtubule depolymerization, with subsequent elevated expression/stabilization of survivin. We investigated the administration of survivin suppressant YM155 monobromide (YM155), in combination with docetaxel, in a human non-small-cell lung cancer (NSCLC) xenograft model. Animals received a 7-day continuous infusion of YM155, 2 mg/kg, and/or three bolus doses of docetaxel, 20 mg/kg, according to three dosing schedules: YM155 administered concomitantly with docetaxel, before docetaxel, and after docetaxel. YM155 administered either concomitantly with or before docetaxel showed significant antitumor activity (tumor regression ≥99%), with complete regression of the established human NSCLC-derived tumors in mice (eight of eight and seven of eight animals, respectively). Significantly fewer complete responses (three of eight animals) were achieved when YM155 was administered after docetaxel. No statistically significant decreases in body weight were observed in the combination versus docetaxel groups. YM155 administered concomitantly with docetaxel resulted in significant decreases in mitotic and proliferative indices, and in a significant increase in the apoptosis index. Elevated survivin expression was seen in tumors from mice treated with docetaxel alone; a significant reduction in survivin expression was seen in tumors from mice treated with YM155 alone or in combination with docetaxel, but not in the control group. These results indicate that in a human NSCLC xenograft model YM155 in combination with docetaxel diminished the accumulation of survivin by docetaxel and induced more intense apoptosis and enhanced antitumor activity, compared with single-agent YM155 or docetaxel. [ source: Anticancer Drugs. 2011 Jun;22(5):454-62. YM155, a novel survivin suppressant, enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model. Nakahara T, Yamanaka K, Hatakeyama S, Kita A, Takeuchi M, Kinoyama I, Matsuhisa A, Nakano K, Shishido T, Koutoku H, Sasamata M. Institute for Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan]
YM155 enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model.
[ source: Anticancer Drugs. 2011 Jun;22(5):454-62. YM155, a novel survivin suppressant, enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model. Nakahara T, Yamanaka K, Hatakeyama S, Kita A, Takeuchi M, Kinoyama I, Matsuhisa A, Nakano K, Shishido T, Koutoku H, Sasamata M. Institute for Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan]
   
   
Data published in Jan 2011
Data published in Jan 2011
Antitumor effects of YM155 against human aggressive non-Hodgkin lymphoma. YM155, a novel small-molecule that down-regulates survivin, exhibits broad, potent antitumor activity against a range of human tumors. We evaluated the activity of YM155 in aggressive non-Hodgkin lymphoma. In a number of diffuse large B-cell lymphoma lines, YM155 exhibited 50% growth inhibition with values between 0.23 and 3.9nM. Within in vivo xenograft models, continuous infusion of YM155 eradicated large, established subcutaneous WSU-DLCL-2 and Ramos tumors, with sustained efficacy observed through 4 cycles of YM155 therapy. YM155 increased survival significantly versus rituximab in disseminated Ramos models. This study suggests that YM155 may represent an effective treatment for aggressive lymphomas. [source: Leuk Res. 2011 Jan 13. [Epub ahead of print] Antitumor effects of YM155, a novel survivin suppressant, against human aggressive non-Hodgkin lymphoma. Kita A, Nakahara T, Yamanaka K, Nakano K, Nakata M, Mori M, Kaneko N, Koutoku H, Izumisawa N, Sasamata M. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.]
Antitumor effects of YM155 against human aggressive non-Hodgkin lymphoma.
YM155, a novel small-molecule that down-regulates survivin, exhibits broad, potent antitumor activity against a range of human tumors. We evaluated the activity of YM155 in aggressive non-Hodgkin lymphoma. In a number of diffuse large B-cell lymphoma lines, YM155 exhibited 50% growth inhibition with values between 0.23 and 3.9nM. Within in vivo xenograft models, continuous infusion of YM155 eradicated large, established subcutaneous WSU-DLCL-2 and Ramos tumors, with sustained efficacy observed through 4 cycles of YM155 therapy. YM155 increased survival significantly versus rituximab in disseminated Ramos models. This study suggests that YM155 may represent an effective treatment for aggressive lymphomas. [source: Leuk Res. 2011 Jan 13. [Epub ahead of print] Antitumor effects of YM155, a novel survivin suppressant, against human aggressive non-Hodgkin lymphoma. Kita A, Nakahara T, Yamanaka K, Nakano K, Nakata M, Mori M, Kaneko N, Koutoku H, Izumisawa N, Sasamata M. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.]
  
  
Data published in March 2011
Data published in March 2011
Broad spectrum and potent antitumor activities of YM155 in a wide variety of human cancer cell lines and xenograft models.  Antitumor activities of YM155, a novel small-molecule survivin suppressant, were investigated in a wide variety of human cancer cell lines and xenograft models. YM155 inhibited the growth of 119 human cancer cell lines, with the greatest activity 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. The mean log growth inhibition of 50% (GI(50) ) value was 15 nM. The mean GI(50) values of YM155 were 11 nM for p53 mut/null cell lines and 16 nM for p53 WT cell lines, suggesting that YM155 inhibits the growth of human tumor cell lines regardless of their p53 status. In non-small-cell lung cancer (Calu 6, NCI-H358), melanoma (A375), breast cancer (MDA-MB-231) and bladder cancer (UM-UC-3) xenograft models, 3- or 7-day continuous infusions of YM155 (1-10 mg/kg) demonstrated significant antitumor activity without showing significant bodyweight loss. Tumor regressions induced by YM155 were associated with reduced intratumoral survivin expression levels, increased apoptosis and decreased mitotic indices. The broad and potent antitumor activity presented in the present study is indicative of the therapeutic potential of YM155 in the clinical setting. [source: Cancer Sci. 2011 Mar;102(3):614-21. Broad spectrum and potent antitumor activities of YM155, a novel small-molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models. Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Kinoyama I, Matsuhisa A, Kudou M, Sasamata M. Institute for Drug Discovery Research, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan. takahito.nakahara@jp.astellas.com]
Broad spectrum and potent antitumor activities of YM155 in a wide variety of human cancer cell lines and xenograft models.  
[source: Cancer Sci. 2011 Mar;102(3):614-21. Broad spectrum and potent antitumor activities of YM155, a novel small-molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models. Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Kinoyama I, Matsuhisa A, Kudou M, Sasamata M. Institute for Drug Discovery Research, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan. takahito.nakahara@jp.astellas.com]
 
 
Data published in Feb 2011
Data published in Feb 2011
A multi-center phase II evaluation of  YM155 in patients with unresectable stage III or IV melanoma.
A multi-center phase II evaluation of  YM155 in patients with unresectable stage III or IV melanoma.
Melanoma continues to be a major health problem with no effective therapy. Melanocytes, both benign and malignant, express many anti-apoptotic factors. Survivin is a member of the family of inhibitors of apoptosis proteins (IAP) and is preferentially expressed in tumor cells, including melanoma. YM155 is a small molecule suppressant of survivin that has been shown in preclinical cell lines, xenograft models and phase I studies to have anti-tumor activity. CONCLUSIONS: YM155 was well tolerated in subjects with advanced melanoma; however, the pre-specified primary end-point for efficacy which required two responders in 29 evaluable subjects was not achieved. [ source: Invest New Drugs. 2011 Feb;29(1):161-6. Epub 2009 Oct 15. A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. Lewis KD, Samlowski W, Ward J, Catlett J, Cranmer L, Kirkwood J, Lawson D, Whitman E, Gonzalez R. University of Colorado Health Sciences Center, Aurora, CO, USA. karl.lewis@ucdenver.edu]
Melanoma continues to be a major health problem with no effective therapy. Melanocytes, both benign and malignant, express many anti-apoptotic factors. Survivin is a member of the family of inhibitors of apoptosis proteins (IAP) and is preferentially expressed in tumor cells, including melanoma. YM155 is a small molecule suppressant of survivin that has been shown in preclinical cell lines, xenograft models and phase I studies to have anti-tumor activity. CONCLUSIONS: YM155 was well tolerated in subjects with advanced melanoma; however, the pre-specified primary end-point for efficacy which required two responders in 29 evaluable subjects was not achieved. [ source: Invest New Drugs. 2011 Feb;29(1):161-6. Epub 2009 Oct 15. A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. Lewis KD, Samlowski W, Ward J, Catlett J, Cranmer L, Kirkwood J, Lawson D, Whitman E, Gonzalez R. University of Colorado Health Sciences Center, Aurora, CO, USA. karl.lewis@ucdenver.edu]
  
Data Published in Sept 2009
Multicenter phase II trial of YM155 in patients with advanced, refractory, non-small-cell lung cancer.
Multicenter phase II trial of YM155 in patients with advanced, refractory, non-small-cell lung cancer.
PURPOSE:  To evaluate the antitumor activity and safety of YM155, a novel, small-molecule suppressor of survivin, as single-agent therapy in patients with previously treated, advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIb/IV NSCLC who had experienced treatment failure during one or two prior chemotherapy regimens (at least one of which was platinum based) received YM155 as a continuous intravenous infusion (4.8 mg/m(2)/d) over 168 hours followed by observation for 14 days in 21-day treatment cycles. The primary end point was objective tumor response rate (ORR). Secondary end points included duration of stable disease (SD), progression-free survival (PFS), overall survival (OS), safety and pharmacokinetic profiles, and pharmacodynamic evaluations.  RESULTS: Thirty-seven patients received YM155. Two patients achieved a confirmed partial response, with an ORR of 5.4% (95% CI, 0.7% to 18.2%). An additional 14 patients (37.8%) achieved SD resulting in a disease control rate of 43.2% (95% CI, 27.1% to 60.5%). Median duration of PFS was 1.7 months (95% CI, 1.3 to 2.8 months). Median duration of OS was 6.6 months (95% CI, 4 to 12.2 months), with a 1-year survival rate of 35.1%. Treatment with YM155 was well tolerated with the majority of treatment discontinuations not treatment related. CONCLUSION: YM155 exhibited modest single-agent activity in patients with refractory, advanced NSCLC. A favorable safety/tolerability profile was reported. Further evaluation of YM155 in combination with chemotherapy and other targeted agents may be warranted. [source: J Clin Oncol. 2009 Sep 20;27(27):4481-6. Epub 2009 Aug 17. Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. Giaccone G, Zatloukal P, Roubec J, Floor K, Musil J, Kuta M, van Klaveren RJ, Chaudhary S, Gunther A, Shamsili S.  Vrije Universiteit Medical Center, Amsterdam, The Netherlands. giacconeg@mail.nih.gov]
PURPOSE:  To evaluate the antitumor activity and safety of YM155, a novel, small-molecule suppressor of survivin, as single-agent therapy in patients with previously treated, advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIb/IV NSCLC who had experienced treatment failure during one or two prior chemotherapy regimens (at least one of which was platinum based) received YM155 as a continuous intravenous infusion (4.8 mg/m(2)/d) over 168 hours followed by observation for 14 days in 21-day treatment cycles. The primary end point was objective tumor response rate (ORR). Secondary end points included duration of stable disease (SD), progression-free survival (PFS), overall survival (OS), safety and pharmacokinetic profiles, and pharmacodynamic evaluations.  RESULTS: Thirty-seven patients received YM155. Two patients achieved a confirmed partial response, with an ORR of 5.4% (95% CI, 0.7% to 18.2%). An additional 14 patients (37.8%) achieved SD resulting in a disease control rate of 43.2% (95% CI, 27.1% to 60.5%). Median duration of PFS was 1.7 months (95% CI, 1.3 to 2.8 months). Median duration of OS was 6.6 months (95% CI, 4 to 12.2 months), with a 1-year survival rate of 35.1%. Treatment with YM155 was well tolerated with the majority of treatment discontinuations not treatment related. CONCLUSION: YM155 exhibited modest single-agent activity in patients with refractory, advanced NSCLC. A favorable safety/tolerability profile was reported. Further evaluation of YM155 in combination with chemotherapy and other targeted agents may be warranted. [source: J Clin Oncol. 2009 Sep 20;27(27):4481-6. Epub 2009 Aug 17. Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. Giaccone G, Zatloukal P, Roubec J, Floor K, Musil J, Kuta M, van Klaveren RJ, Chaudhary S, Gunther A, Shamsili S.  Vrije Universiteit Medical Center, Amsterdam, The Netherlands. giacconeg@mail.nih.gov]
 
 
Data published in 2008
Data published in 2008
Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin.   PURPOSE: To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin. PATIENTS AND METHODS: Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion. RESULTS: Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response.  CONCLUSION: YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors. [source: J Clin Oncol. 2008 Nov 10;26(32):5198-203. Epub 2008 Sep 29.  Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. Tolcher AW, Mita A, Lewis LD, Garrett CR, Till E, Daud AI, Patnaik A, Papadopoulos K, Takimoto C, Bartels P, Keating A, Antonia S. Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA. atolcher@start.stoh.com]
Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin.   PURPOSE: To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin. PATIENTS AND METHODS: Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion. RESULTS: Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response.  CONCLUSION: YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors. [source: J Clin Oncol. 2008 Nov 10;26(32):5198-203. Epub 2008 Sep 29.  Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. Tolcher AW, Mita A, Lewis LD, Garrett CR, Till E, Daud AI, Patnaik A, Papadopoulos K, Takimoto C, Bartels P, Keating A, Antonia S. Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA. atolcher@start.stoh.com]