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 15 nM. The mean GI50 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. (Cancer Sci 2011; 102: 614–621)
Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, ...including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed 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. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations approximately 20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach.
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.
► p54nrb binds to the survivin promoter and regulates survivin expression. ► p54nrb physically interacts with ILF3 through RNA. ► YM155 induces disruption of the ILF3/p54nrb complex.
YM155, a ...small-molecule survivin suppressant, specifically binds to the transcription factor ILF3, which regulates the expression of survivin1. In this experiment we have demonstrated that p54nrb binds to the survivin promoter and regulates survivin expression. p54nrb forms a complex with ILF3, which directly binds to YM155. YM155 induces disruption of the ILF3/p54nrb complex, which results in a different subcellular localization between ILF3 and p54nrb. 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.
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.
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).
The IC50 of YM-359445 for VEGFR2 tyrosine kinase was 0.0085 micromol/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 micromol/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.
Our results show that YM-359445 is more potent than orally bioavailable VEGFR2 tyrosine kinase inhibitors, which leads to great expectations for clinical applicability.
Chemotherapy using anticancer drugs induces serious the problem of multidrug resistance (MDR) in the cancer cells. In contrast, endothelial cells so rarely acquire MDR that antiangiogenesis therapy ...has recently been considered as an effective means for cancer chemotherapy. We screened compounds in the chemical library to find a novel and orally active antitumor agent with vascular endothelial growth factor receptor-2 tyrosine kinase (VEGF-R2 TK) inhibition. The result was YM-231146 (IC50=0.080 μM). YM-231146 inhibited VEGF-stimulated proliferation, VEGF-R2 autophosphorylation, and vessel sprout formation of human vascular endothelial cells at concentrations between 0.15—0.30 μM. However, YM-231146 did not inhibit cancer cell proliferation at these concentrations (IC50>5 μM). In the in vivo studies, once-daily oral dosing of YM-231146 to human cancer xenografts elicited antitumor activity at doses of 3—100 mg/kg. Moreover, YM-231146 completely inhibited tumor growth of paclitaxel-resistant cancer cells without decreasing body weight at a dose of 100 mg/kg. These results suggest that YM-231146 is a novel orally bioavailable inhibitor of VEGF-R2 that would be useful for the treatment of multidrug resistant tumors.
YM155, a small-molecule survivin suppressant, specifically binds to the transcription factor ILF3, which regulates the expression of survivin1. 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.
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.
To find a new series of arginine vasopressin (AVP) V1A receptor antagonists, the influence of the 2-phenyl group of 2-phenyl-4′-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzanilide (7) was ...investigated. Replacement of the 2-phenyl group by a 2-ethyl-1H-imidazol-1-yl group was effective in yielding a V1A-selective compound. Moreover, this imidazolyl group was introduced in the same position in YM-35471 (6), and further studies of these compounds were performed. Consequently, we found that the (Z)-4′-({4,4-difluoro-5-(N-cyclopropylcarbamoyl)methylene-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-yl)benzanilide (9f) exhibited highly potent affinity and selectivity, and was the most potent antagonist for the V1A receptor among our compounds. The synthesis and pharmacological evaluation of these compounds are described in this paper
Stereoselective synthesis of methyl (Z)-(4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene)acetate (1a) is described. Z-selectivity of the Horner–Wadsworth–Emmons (HWE) reaction was obtained ...based on an investigation of the reaction conditions for introduction of a methylidene group onto the 5-position of benzazepine.
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