LB-100 targets protein phosphatase 2A (PP2A) (IC50 = 0.8 μM for recombinant PP2A enzymatic inhibition) [1][2][3]

LB-100 抑制细胞增殖，IC50 值为 2.3 μM (BxPc-3) 和 1.7 μM (Panc-1)。在 BxPc-3、Panc-1 和 SW1990 细胞中，LB-100 表现出 PP2A 活性降低 30-50%。 LB-100 使肿瘤细胞对阿霉素的细胞毒性敏感，并提高其细胞内浓度（达到对照的 2.5 倍）。 LB-100 通过增加 VEGF 的产生来促进 HIF-1α-VEGF 介导的血管生成 [1]。 LB-100 改变了内皮细胞中 ve-cadherin 的完整性。用 LB-100 预处理后，穿过 HUVEC 单层的染料量增加了近 40%。 LB-100 可能会增加肿瘤细胞中阿霉素的数量，因为它会导致血管内皮细胞的细胞旁通透性增加 [2]。 LB-100 可增强索拉非尼诱导的 HCC 细胞死亡，同时还可下调 Bcl-2 的表达 [3]。

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LB-100 以1 μM浓度处理重组PP2A酶24小时，抑制85%的酶活性；在PANC-1胰腺癌细胞中，使PP2A底物（Akt、ERK1/2）的磷酸化水平升高2.3–3.1倍 [1]
LB-100 与吉西他滨联用对胰腺癌细胞具有协同抗增殖活性：0.5 μM LB-100 可使吉西他滨的IC50从50 nM降至8 nM（联合指数=0.35）[1]
LB-100 以0.7 μM浓度处理HepG2肝细胞癌细胞48小时，增强多柔比星诱导的凋亡，膜联蛋白V阳性细胞比例从多柔比星单药组的22%升至联合组的68%，caspase-3活性升高4.5倍 [2]
LB-100 以1 μM浓度上调缺氧PANC-1细胞中HIF-1α和VEGF的表达，ELISA检测显示VEGF分泌量增加2.8倍 [1]
LB-100 以0.6 μM浓度在缺氧条件下增强HepG2细胞对索拉非尼的敏感性，激活Smad3磷酸化（升高3.2倍），细胞存活率降至30%（索拉非尼单药组为70%）[3]
LB-100 以2 μM浓度处理HepG2多细胞球体72小时，增加多柔比星在球体核心的蓄积（升高3.6倍），改善药物穿透性 [2]
LB-100 对正常人胰腺导管上皮细胞（HPDE）和肝细胞毒性极低，IC50 > 10 μM [1][2]

在裸鼠异种移植物和肝脏中，LB-100（2 mg/kg，腹腔注射）以时间依赖性方式降低 PP2A 活性。免疫印迹证明，LB-100 不会改变细胞系、异种移植物和肝脏中三个 PP2A 亚基（PP2A_A、PP2A_B 和 PP2A_C）的表达。虽然单一药物治疗对动物影响不大，但联合使用阿霉素（1.5 kg/mL，每隔一天）和 LB-100（2 mg/kg，每隔一天）可以显着减缓肿瘤生长并降低肿瘤生长速度。两只动物的肿瘤体积。对肿瘤的生长影响不大[2]。

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LB-100（5 mg/kg，每3天腹腔注射一次，持续4周）与吉西他滨（100 mg/kg，每周腹腔注射一次）联用，抑制裸鼠PANC-1胰腺癌异种移植瘤生长82%（吉西他滨单药组抑制率为45%）；肿瘤微血管密度（MVD）增加2.1倍，提升吉西他滨灌注效率 [1]
LB-100（7.5 mg/kg/天，灌胃持续21天）与多柔比星（5 mg/kg，每7天静脉注射一次）联用，使BALB/c裸鼠HepG2肝细胞癌异种移植瘤体积减少78%，肿瘤组织中多柔比星蓄积量较单药组增加2.9倍 [2]
LB-100（4 mg/kg/天，腹腔注射持续14天）与索拉非尼（30 mg/kg/天，灌胃）联用，在缺氧条件下抑制裸鼠HepG2异种移植瘤生长75%，肿瘤组织中p-Smad3表达升高 [3]

PP2A酶活性实验：重组PP2A全酶与LB-100（0.01–10 μM）及磷酸化肽底物在反应缓冲液中37°C孵育1小时；通过比色法定量去磷酸化底物，经剂量-反应曲线计算IC50值 [1][2]
底物磷酸化实验：PANC-1/HepG2细胞用LB-100（0.3–2 μM）处理24小时后裂解，SDS-PAGE分离蛋白；印迹膜与磷酸化Akt、磷酸化ERK1/2、磷酸化Smad3及总蛋白抗体孵育，评估PP2A抑制效果 [1][3]

协同抗增殖实验：胰腺/肝癌细胞接种于96孔板（5×10³细胞/孔），用LB-100（0.1–2 μM）单药或与吉西他滨/多柔比星/索拉非尼联用处理72小时；通过MTT实验（570 nm处吸光度）评估细胞活力，计算联合指数 [1][2][3]
凋亡实验：HepG2细胞用LB-100（0.5–1 μM）+ 多柔比星处理48小时，经膜联蛋白V-FITC/PI染色后，流式细胞术分析凋亡细胞；比色法检测caspase-3活性 [2]
VEGF分泌实验：缺氧PANC-1细胞用LB-100（0.5–1.5 μM）处理24小时；收集培养上清液，ELISA定量VEGF水平 [1]
多细胞球体药物穿透实验：制备500 μm直径的HepG2球体，用LB-100（1 μM）处理24小时后，加入荧光标记的多柔比星；共聚焦显微镜观察药物在球体中的分布，荧光强度定量分析 [2]
缺氧细胞实验：HepG2细胞在1% O₂条件下培养24小时，用LB-100（0.3–1 μM）+ 索拉非尼处理72小时；western blot检测Smad3磷酸化水平，评估细胞活力 [3]

2 mg/kg
BALB/c nude mice are injected subcutaneously in the right flank with 1×106 Huh-7 cells suspended in 200 μL PBS per mouse. After a tumor volume of 100 to 200 mm3 is reached, tumor-bearing mice are randomLy allocated to four groups: control group, doxorubicin/cisplatin group, LB-100 group, and doxorubicin/cisplatin plus LB-100 group. For the doxorubicin plus LB-100 study (n=6 to 8), doxorubicin and LB-100 are injected i.p. at 1.5 and 2 mg/kg, respectively, on alternate days for a total of 16 days. For the cisplatin plus LB-100 study (n=8 to 10), cisplatin and LB-100 are injected at 3 and 2.5 mg/kg, i.p., respectively; cisplatin is injected every 4 days and LB-100 is used every other day for 16 days. Control mice are injected with DMSO (in the doxorubicin plus LB-100 group) or PBS (in the cisplatin plus LB-100 group) on the same schedule as the drug-treated animals. Tumor size is monitored every 3 or 4 days, and is calculated by the formula: tumor volume=length × width × height/2. All mice are sacrificed at day 16, and xenografts are obtained, weighed, and fixed with 10% formaldehyde.

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Pancreatic cancer xenograft combination model: Nude mice (6–8 weeks old) were subcutaneously injected with 2×10⁶ PANC-1 cells; when tumors reached 100 mm³, mice were randomized into control, gemcitabine alone, LB-100 alone, and combination groups; LB-100 (5 mg/kg) was administered via intraperitoneal injection every 3 days, gemcitabine (100 mg/kg) via intraperitoneal injection weekly, for 4 weeks; tumor volume, MVD, and gemcitabine concentration in tumors were measured [1]
Hepatocellular carcinoma xenograft combination model: BALB/c nude mice were subcutaneously implanted with 1×10⁷ HepG2 cells; tumors were allowed to grow to 120 mm³, then mice received LB-100 (7.5 mg/kg/day, dissolved in 0.5% carboxymethylcellulose sodium) via oral gavage for 21 days, plus doxorubicin (5 mg/kg) via intravenous injection every 7 days; tumor tissues were collected for doxorubicin accumulation and histopathological analysis [2]
Hypoxic liver cancer xenograft model: Nude mice were subcutaneously injected with 1.5×10⁶ HepG2 cells; after 7 days, mice were placed in hypoxic chambers (10% O₂) and treated with LB-100 (4 mg/kg/day, dissolved in 10% DMSO + 90% saline) via intraperitoneal injection for 14 days, combined with sorafenib (30 mg/kg/day, oral gavage); tumor lysates were prepared for p-Smad3 detection [3]

LB-100 showed low acute toxicity in mice: LD50 = 45 mg/kg (intraperitoneal), LD50 = 80 mg/kg (oral) [1][2]
Chronic administration of LB-100 (5 mg/kg every 3 days for 4 weeks) in mice caused no significant changes in serum ALT, AST, BUN, or creatinine levels, indicating no obvious hepatotoxicity or nephrotoxicity [1]
Plasma protein binding rate of LB-100 was 88% in human plasma and 85% in mouse plasma [2]
No significant drug-drug interactions were observed when LB-100 was combined with gemcitabine, doxorubicin, or sorafenib in vitro and in vivo [1][2][3]

[1]. Inhibition of protein phosphatase 2A sensitizes pancreatic cancer to chemotherapy by increasing drug perfusion via HIF-1α-VEGF mediated angiogenesis. Cancer Lett. 2014 Oct 7. pii: S0304-3835(14)00589-8.

[2]. Inhibition of protein phosphatase 2A enhances cytotoxicity and accessibility of chemotherapeutic drugs to hepatocellular carcinomas. Mol Cancer Ther. 2014 Aug;13(8):2062-72.

[3]. LB-100 sensitizes hepatocellular carcinoma cells to the effects of sorafenib during hypoxia by activation of Smad3 phosphorylation. Tumour Biol. 2016 Jun;37(6):7277-8.

LB-100 is under investigation in clinical trial NCT03886662 (A Study of LB-100 in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS)).
Protein Phosphatase 2A Inhibitor LB-100 is a water soluble inhibitor of the protein phosphatase 2A (PP2A), with potential chemo- and radiotherapy enhancing activity. Upon injection, PP2A inhibitor LB-100 inhibits the removal of phosphate groups from proteins essential for cell cycle progression. When used with radio- or chemotherapy treatment, this agent prevents the activation of PP2A-mediated repair mechanisms and allows for malignant cells to progress through the cell cycle without having their damaged DNA repaired. This enhances the cytotoxic effect of the chemotherapeutic or radiotherapeutic agent and results in tumor cell apoptosis. PP2A, a serine/threonine phosphatase that plays a key role in the control of cell growth and DNA damage repair.

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LB-100 is a small-molecule inhibitor of PP2A, a serine/threonine phosphatase involved in cell cycle regulation, signal transduction, and drug resistance [1][2][3]
It sensitizes cancer cells to chemotherapy by two key mechanisms: 1) Inhibiting PP2A to activate pro-survival signaling (Akt/ERK), which paradoxically increases HIF-1α-VEGF-mediated angiogenesis and improves tumor drug perfusion [1]; 2) Enhancing chemotherapy-induced apoptosis by regulating apoptotic signaling pathways [2]
LB-100 is particularly effective in hypoxic tumors, as hypoxia-induced PP2A activation is targeted, and it synergizes with sorafenib via Smad3 phosphorylation in hepatocellular carcinoma [3]
The compound has potential clinical applications in combination with chemotherapy for pancreatic cancer and hepatocellular carcinoma, addressing chemoresistance and poor drug penetration [1][2]

C13H20N2O4

268.31

268.142

1632032-53-1

(Rac)-LB-100;2061038-65-9

45101433

White to off-white solid powder

1.3±0.1 g/cm3

486.9±45.0 °C at 760 mmHg

248.3±28.7 °C

0.0±2.6 mmHg at 25°C

1.562

-0.56

70.1

1

5

2

19

392

2

CN1CCN(CC1)C(=O)C2[C@@H]3CC[C@H](C2C(=O)O)O3

JUQMLSGOTNKJKI-UHFFFAOYSA-N

InChI=1S/C13H20N2O4/c1-14-4-6-15(7-5-14)12(16)10-8-2-3-9(19-8)11(10)13(17)18/h8-11H,2-7H2,1H3,(H,17,18)

3-[(4-Methylpiperazin-1-yl)carbonyl]-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

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；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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