Akira Matsuhisa

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

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% (GI50) value was 15u2003nM. The mean GI50 values of YM155 were 11u2003nM for p53 mut/null cell lines and 16u2003nM 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 (1–10u2003mg/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. (Cancer Sci 2011; 102: 614–621)

Sepantronium Bromide (YM155) induces disruption of the ILF3/p54nrb complex, which is required for survivin expression

YM155, a small-molecule survivin suppressant, specifically binds to the transcription factor ILF3, which regulates the expression of survivin[1]. In this experiment we have demonstrated that p54(nrb) binds to the survivin promoter and regulates survivin expression. p54(nrb) forms a complex with ILF3, which directly binds to YM155. YM155 induces disruption of the ILF3/p54(nrb) complex, which results in a different subcellular localization between ILF3 and p54(nrb). Thus, identification of molecular targets of YM155 in suppression of the survivin pathway, might lead to development of its use as a novel potential target in cancers.

Interleukin Enhancer-binding Factor 3/NF110 Is a Target of YM155, a Suppressant of Survivin

Survivin is responsible for cancer progression and drug resistance in many types of cancer. YM155 selectively suppresses the expression of survivin and induces apoptosis in cancer cells in vitro and in vivo. However, the mechanism underlying these effects of YM155 is unknown. Here, we show that a transcription factor, interleukin enhancer-binding factor 3 (ILF3)/NF110, is a direct binding target of YM155. The enhanced survivin promoter activity by overexpression of ILF3/NF110 was attenuated by YM155 in a concentration-dependent manner, suggesting that ILF3/NF110 is the physiological target through which YM155 mediates survivin suppression. The results also show that the unique C-terminal region of ILF3/NF110 is important for promoting survivin expression and for high affinity binding to YM155.

YM-359445, an Orally Bioavailable Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor, Has Highly Potent Antitumor Activity against Established Tumors

Purpose: The vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase has been implicated in the pathologic angiogenesis associated with tumor growth. YM-359445 was a (3Z)-3-quinolin-2(1H)-ylidene-1,3-dihydro-2H-indol-2-one derivative found while screening based on the inhibition of VEGFR2 tyrosine kinase. The aim of this study was to analyze the efficacy of this compound both in vitro and in vivo. Experimental Design: We tested the effects of YM-359445 on VEGFR2 tyrosine kinase activity, cell proliferation, and angiogenesis. The antitumor activity of YM-359445 was also tested in nude mice bearing various established tumors and compared with other VEGFR2 tyrosine kinase inhibitors (ZD6474, CP-547632, CGP79787, SU11248, and AZD2171), a cytotoxic agent (paclitaxel), and an epidermal growth factor receptor tyrosine kinase inhibitor (gefitinib). Results: The IC50 of YM-359445 for VEGFR2 tyrosine kinase was 0.0085 μmol/L. In human vascular endothelial cells, the compound inhibited VEGF-dependent proliferation, VEGFR2 autophosphorylation, and sprout formation at concentrations of 0.001 to 0.003 μmol/L. These concentrations had no direct cytotoxic effect on cancer cells. In mice bearing various established tumors, including paclitaxel-resistant tumors, once daily oral administration of YM-359445 at doses of 0.5 to 4 mg/kg not only inhibited tumor growth but also reduced its vasculature. YM-359445 had greater antitumor activity than other VEGFR2 tyrosine kinase inhibitors. Moreover, in human lung cancer A549 xenografts, YM-359445 markedly regressed the tumors (73%) at a dose of 4 mg/kg, whereas gefitinib caused no regression even at 100 mg/kg. Conclusion: Our results show that YM-359445 is more potent than orally bioavailable VEGFR2 tyrosine kinase inhibitors, which leads to great expectations for clinical applicability.

Abstract 4756: YM155 suppresses survivin expression by disrupting the ILF3/p54nrb transcription factor complex

Survivin, a member of the anti-apoptosis proteins family, is highly expressed in all primary tumor types, and is responsible for cancer progression and drug resistance in many types of cancer. YM155, a small chemical compound, selectively suppressed the expression of survivin and induced apoptosis in cancer cells both in vitro and in vivo. However, the mechanisms underlying the suppression of survivin expression by YM155 are unknown. In order to identify the molecular targets and analyze the drug mechanism of action, affinity purification was performed using an active analogue of YM155. We identified interleukin enhancer-binding factor 3 (ILF3) as the binding target of YM155. From the complex analysis of ILF3 and survivin promoter sequence, we also found that ILF3 forms a complex with p54nrb transcription factor, and then binds to the survivin promoter. Overexpression of ILF3 enhanced survivin promoter activity, which was attenuated by YM155 in a concentration-dependent manner. Furthermore, the ILF3/p54nrb complex was disrupted by YM155, thus dispersing the components in the nucleus.In conclusion, our study suggests that binding to ILF3 by YM155 causes the dissociation of the ILF3/p54nrb complex, thus inhibits ILF3 dependent survivin expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4756. doi:1538-7445.AM2012-4756