ERα (IC50 = 26 nM); ERβ (IC50 = 99 nM)[1]

小分子 GP130 抑制剂盐酸苯多昔芬与 GP130 D1 结构域相互作用[1]。在 GP130/STAT3 通路信号传导中，盐酸苯二氮卓抑制由 IL-6 和 IL-11 触发的 STAT3 磷酸化[1]。在人胰腺癌细胞中，盐酸苯二氮卓（10 μM–20 μM；2 小时）可抑制细胞因子引起的 STAT3 磷酸化[2]。盐酸巴多昔芬（5–20 μM；过夜给药）会导致人胰腺癌细胞凋亡[2]。 IL-6 诱导的 STAT3 核转位被盐酸苯多昔芬抑制[2]。通过抑制 GP130，盐酸苯多昔芬可防止胰腺癌细胞迁移[2]。

在未成熟大鼠子宫模型中， 巴多昔芬0.5和5.0 mg/kg)对子宫湿重的增加作用小于乙炔雌二醇(10微克/kg)或雷洛昔芬(0.5和5.0 mg/kg)。组织学分析显示，同时使用巴多昔芬也能减少雷洛昔芬刺激的子宫内膜上皮细胞和子宫肌层细胞肥大。在去卵巢大鼠中，与对照组相比，巴多昔芬与6周时骨矿物质密度显著增加有关，与去卵巢动物的样本相比，L4椎骨样本的抗压强度更好。在吗啡成瘾大鼠血管舒缩活性模型中，单独使用保骨剂量的巴多昔芬与17 - β -雌二醇对血管舒缩活性增加的抑制作用无关。醋酸巴多昔芬是一种很有前景的治疗骨质疏松症的新方法，与目前临床上使用的选择性雌激素受体调节剂相比，它对子宫和血管舒缩的影响可能更小。需要对照临床试验数据来证实这些效果。

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巴泽多昔芬抑制小鼠体内模型capan-1肿瘤生长[2]
在小鼠模型中，醋酸巴多昔芬(5 mg/kg;搞笑;每日，持续18天)在体内抑制Capan-1肿瘤生长[2]。
在本研究中，研究人员验证了巴多昔芬是否在体内和体外抑制肿瘤生长。Capan-1细胞(3 × 106)注射方法如前面材料和方法所述。初始植入1周后，当肿瘤大小达到0.05 ~ 0.1cm3时，给予治疗组巴多昔芬5 mg/kg，对照组给予DMSO，连续18 d。如图6A所示，与载药组相比，巴多昔芬明显抑制肿瘤生长。巴多昔芬处理组肿瘤组织样本P-STAT3Y705降低，caspase-3被诱导(图6A)，提示巴多昔芬可以抑制胰腺癌异种移植瘤的生长，诱导肿瘤细胞凋亡。

配体结合[1]
使用先前描述的[3H]-17β-雌二醇，采用固相竞争放射配体结合法评估醋酸巴多昔芬(BZA)与人ERα和ERβ的相互作用。

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STAT3 DNA结合试验[2]
将BxPC-3细胞接种于10cm板上，用5-10 μmol/L的巴多昔芬或DMSO处理24h。细胞核提取试剂盒 按照制造商的方案制备细胞核提取液。采用STAT3 DNA结合ELISA试剂盒(Active Motif)，采用ELISA方法分析核提取物的STAT3 DNA结合活性。在450nm处读取吸光度。

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细胞因子或生长因子诱导STATs磷酸化[2]
将PANC-1、AsPC-1和hpf - ii胰腺癌细胞接种于10厘米板中，留置过夜。第二天晚上，这些细胞被血清饥饿。然后不处理细胞或用巴泽多西芬(5 ~ 20 μmol/L)或DMSO处理细胞。2小时后，未处理和巴多昔芬处理的细胞被IL6 (50 ng/mL)、IL11 (50 ng/mL)、OSM (50 ng/mL)或INFγ (50 ng/mL)刺激30分钟。收集细胞，用Western blot分析p-STAT3Y705或p-STAT1Y701。

蛋白质印迹分析[2]
细胞类型： AsPC-1 细胞
测试浓度： 10 μM、20 μM
孵育时间： 2 小时
实验结果： 抑制 IL-6、IL-11 或 OSM (50 ng/mL) 诱导的 STAT3 磷酸化。

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细胞凋亡分析[2]
细胞类型： Capan-1 细胞、BxPC-3 细胞、HPAF-II 细胞、HPAC 细胞
测试浓度： 10μM、20μM（Capan-1）； 5μM、10μM（BxPC-3）； 10 μM、20 μM (HPAF-II)； 10 μM、15 μM (HPAC)
孵育时间：过夜
实验结果：诱导细胞凋亡。

Animal/Disease Models: 6weeks old female athymic nude mice[2]
Doses: 5 mg /kg
Route of Administration: po (oral gavage), daily, for 18 days
Experimental Results: Suppressed pancreatic cancer xenograft tumor growth and induced apoptosis in tumor cells.

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Vasomotor instability (hot flush)[1]
Ovariectomized female (60 d) rats were obtained after surgery. The surgeries were performed minimally 7 d before initiation of any experiment. Vehicle and ethinyl estradiol (0.3 mg/kg) were included in each replicate. Bazedoxifene was administered orally in a saline, Tween-80, methylcellulose vehicle. A detailed description of methodology for evaluating vasomotor instability in rats has been published (21). Briefly, compound treatment (17β-estradiol, ethinyl estradiol, or bazedoxifene) is initiated, and on the third day of treatment each animal receives a morphine pellet sc. This is followed by two more pellets on the fifth day of treatment. On the eighth day, a thermistor is taped to the animal’s tail to measure tail skin temperature for 15 min (to obtain baseline temperature) followed by a sc injection of naloxone (1 mg/kg). Tail skin temperature readings continue for 1 h after naloxone injection.

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Capan-1 (3 × 106) and HPAF-II (3 × 106) cells in Matrigel were injected subcutaneously into the both side of flank area of 6-week-old female athymic nude mice. After Capan-1 tumor development, which was 1 week after initial implantation, mice were divided into two treatment groups consisting of four mice (tumors: n = 8): DMSO vehicle control and gavage injection of Bazedoxifene (5 mg/kg/d). Mice bearing HPAF-II tumor were irrigated with Bazedoxifene(5 mg/kg/d) and/or injected via abdomen with paclitaxel (15 mg/kg, 2/w). Tumor growth was determined by measured the length (L) and width (W) of the tumor every other day with a caliper, and tumor volume was calculated on the basis of the following formula: volume = 0.52 × LW2. After 21 days of treatment, tumors were harvested, snap-frozen in dry ice, and stored at −80°C. Tumors tissue homogenates were lysed and separated by SDS-PAGE to examine the expression of STAT3 phosphorylation, P-ERK1/2, P-AKT (Ser473), and cleaved caspase-3.[2]

[1]. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005 Sep;146(9):3999-4008.

[2]. Bazedoxifene as a Novel GP130 Inhibitor for Pancreatic Cancer Therapy. Mol Cancer Ther. 2016 Nov; 15(11): 2609–2619.

The IL6/GP130/STAT3 pathway is crucial for tumorigenesis in multiple cancer types, including pancreatic cancer, and presents as a viable target for cancer therapy. We reported Bazedoxifene, which is approved as a selective estrogen modulator by FDA, as a novel inhibitor of IL6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL6/GP130/STAT3 signaling in vitro and in vivo In addition, IL6, but not INFγ, rescued Bazedoxifene-mediated reduction of cell viability. Bazedoxifene also inhibited STAT3 phosphorylation induced by IL6 and IL11, but not by OSM or STAT1 phosphorylation induced by INFγ in pancreatic cancer cells, suggesting that Bazedoxifene inhibits the GP130/STAT3 pathway mediated by IL6 and IL11. Furthermore, Bazedoxifene combined with paclitaxel or gemcitabine synergistically inhibited cell viability and cell migration in pancreatic cancer cells. These results indicate that Bazedoxifene is a potential agent and can generate synergism when combined with conventional chemotherapy in human pancreatic cancer cells and tumor xenograft in mice. Therefore, our results support that Bazedoxifene as a novel inhibitor of GP130 signaling and may be a potential and safe therapeutic agent for human pancreatic cancer therapy. [2]

C30H34N2O3.HCL

507.06

506.234

198480-56-7

Bazedoxifene;198481-32-2;Bazedoxifene acetate;198481-33-3

9936012

Typically exists as solid at room temperature

7.07

57.86

3

4

7

36

623

0

CC1=C(C2=CC=C(C=C2)O)N(CC3=CC=C(C=C3)OCCN4CCCCCC4)C5=C1C=C(C=C5)O.Cl

COOWZQXURKSOKE-UHFFFAOYSA-N

InChI=1S/C30H34N2O3.ClH/c1-22-28-20-26(34)12-15-29(28)32(30(22)24-8-10-25(33)11-9-24)21-23-6-13-27(14-7-23)35-19-18-31-16-4-2-3-5-17-31;/h6-15,20,33-34H,2-5,16-19,21H2,1H3;1H

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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