MSI-1436 (Trodusquemine)
(Synonyms: Trodusquemine; Aminosterol-1436) 目录号 : GC32396
MSI-1436 (Trodusquemine)是一种选择性非竞争性的酪氨酸磷酸酶1B (PTB1B) 酶抑制剂。
Cas No.:186139-09-3
Sample solution is provided at 25 µL, 10mM.
MSI-1436 (Trodusquemine) is a selective non-competitive inhibitor of the enzyme protein tyrosine phosphatase 1B (PTB1B). The IC50 of MSI-1436 is about 1 µM, which is 200 times higher than that of TCPTP (IC50, 224 µM). [1]. Besides,it has antimicrobial activity[6].
Incubation of intact HepG2 cells with 10µM MSI-1436 (Trodusquemine) resulted in a 53% inhibition of phosphatase activity compared with control (no inhibitor)[1]. MSI-1436 (Trodusquemine) is a "first-in-class" highly selective inhibitor of PTP1B that can cross the blood-brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. in cultured neuronal cells[2]. Selective inhibition of PTP1B in equine ASC EMS cells improved substantially adipogenic differentiation by promoting cellular proliferation and normalizing expression of C/EBPalpha, PPARγ. Levels of secreted adiponectin and PPARγ were also shown to be increased in MSI-1436 (Trodusquemine)-conditioned cells, while total leptin levels markedly dropped under the same conditions[4].
MSI-1436 (Trodusquemine) acts rapidly and leads to significant weight loss after the first dose. A prerequisite for safe and effective antiobesity therapy is to reduce fat without reducing lean muscle mass Trodusquemine Treated mice had no reduction in whole-body protein content, but smaller epididymal fat pads, reduced adipocyte area in white and brown adipose tissue, and significant reduction in whole-body fat composition fat-specific non-cachexic weight loss in MSI-1436 (Trodusquemine) could explain the dependence of percentage weight loss on initial body weight[1]. A single injection of the drug MSI-1436 (Trodusquemine) decreased food intake in rats. To assess the effects of MSI-1436 (Trodusquemine) on DAT function, fast-scan cyclic voltammetry was used to measure DA concentration changes in the ventral striatum. Neither saline nor MSI-1436 (Trodusquemine) caused a significant change in the magnitude of evoked release from baseline values whereas bupropion caused a significant increase. MSI-1436 (Trodusquemine) as an anti-obesity treatment which spares DAT[5]. MSI-1436 (Trodusquemine) antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer[7]. The PTP1B inhibitor MSI-1436 (Trodusquemine) normalizes PTP1B activity, restores mGluR5 function, and attenuates the anxiety phenotype in LMO4 KO mice [3].
References:
[1]: Lantz KA, Hart SG, et,al. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity (Silver Spring). 2010 Aug;18(8):1516-23. doi: 10.1038/oby.2009.444. Epub 2010 Jan 14. PMID: 20075852.
[2]: Qin Z, Pandey NR, et,al. Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound. Biochem Biophys Res Commun. 2015 Feb 27;458(1):21-7. doi: 10.1016/j.bbrc.2015.01.040. Epub 2015 Jan 24. PMID: 25623533.
[3]: Qin Z, Zhou X, et,al. Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling. Neuron. 2015 Mar 18;85(6):1319-31. doi: 10.1016/j.neuron.2015.02.015. Epub 2015 Mar 5. PMID: 25754825.
[4]: Bourebaba L, Kornicka-Garbowska K, et,al.MSI-1436 improves EMS adipose derived progenitor stem cells in the course of adipogenic differentiation through modulation of ER stress, apoptosis, and oxidative stress. Stem Cell Res Ther. 2021 Feb 3;12(1):97. doi: 10.1186/s13287-020-02102-x. PMID: 33536069; PMCID: PMC7860037.
[5]: Roitman MF, Wescott S, et,al. MSI-1436 reduces acute food intake without affecting dopamine transporter activity. Pharmacol Biochem Behav. 2010 Nov;97(1):138-43. doi: 10.1016/j.pbb.2010.05.010. Epub 2010 May 15. PMID: 20478327; PMCID: PMC2945616.
[6]: Shu Y, Jones SR, et,al. The synthesis of spermine analogs of the shark aminosterol squalamine. Steroids. 2002 Mar;67(3-4):291-304. doi: 10.1016/s0039-128x(01)00161-1. PMID: 11856553.
[7]: Krishnan N, Koveal D, et,al.Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat Chem Biol. 2014 Jul;10(7):558-66. doi: 10.1038/nchembio.1528. Epub 2014 May 20. PMID: 24845231; PMCID: PMC4062594.
MSI-1436 (Trodusquemine)是一种选择性非竞争性的酪氨酸磷酸酶1B (PTB1B) 酶抑制剂。MSI-1436的IC50约为1 µM，比TCPTP (IC50，224 µM)高200倍 [1]。此外，它具有抗微生物活性 [6]。
将完整的HepG2细胞与10µM MSI-1436 (Trodusquemine)孵育，与对照组（无抑制剂）相比，磷酸酶活性被抑制了53% [1]。MSI-1436 (Trodusquemine)是首个可以通过血脑屏障来抑制饮食，促进胰岛素敏感性和血糖控制的"首创类"高选择性PTP1B抑制剂，在培养的神经细胞中有明显效果 [2]。在马ASC EMS细胞中选择性抑制PTP1B可以显著改善脂肪形成的分化，通过促进细胞增殖和正常化C/EBPalpha，PPARγ的表达。MSI-1436 (Trodusquemine)处理的细胞中，分泌的脂联素和PPARγ水平也有所增加，而在同样条件下，总的瘦素水平显著下降 [4]。
MSI-1436 (Trodusquemine)作用迅速，在第一次剂量后导致显著的体重下降。安全有效的抗肥胖治疗的前提是减少脂肪而不减少瘦肌肉量。Trodusquemine处理的小鼠全身蛋白质含量没有减少，但是附睾脂肪垫更小，白色和棕色脂肪组织的脂肪细胞面积减少，以及全身脂肪成分显著减少。MSI-1436 (Trodusquemine)的脂肪特异性非消瘦性体重减轻可以解释体重减轻百分比依赖于初始体重的现象 [1]。一次性注射MSI-1436 (Trodusquemine)药物可以减少大鼠的食物摄取。为了评估MSI-1436 (Trodusquemine)对DAT功能的影响，使用快速扫描循环伏特法测量腹侧纹状体中DA浓度的变化。盐水或MSI-1436 (Trodusquemine)对于从基线值激发的释放幅度都没有造成显著改变，而bupropion则导致了显著增加。MSI-1436 (Trodusquemine)作为一种抗肥胖治疗，保留了DAT [5]。MSI-1436 (Trodusquemine)拮抗HER2信号，抑制了异种移植瘤中的肿瘤生成，并在NDL2乳腺癌小鼠模型中消除了转移，验证了抑制PTP1B作为乳腺癌治疗策略的有效性 [7]。PTP1B抑制剂MSI-1436 (Trodusquemine)能够正常化PTP1B活性，恢复mGluR5功能，并在LMO4 KO小鼠中减轻焦虑表型 [3]。
| Kinase experiment [1]: | |
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Preparation Method |
Human kinases activities were measured using KINOMEscan. In brief, 256 DNA-tagged kinases, ligand affinity beads, and MSI-1436 (Trodusquemine)(10 µmol/l) were incubated at room temperature, washed, and then eluted. Phage titer in the eluates was quantitated by real-time quantitative PCR. |
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Reaction Conditions |
10 µmol/l MSI-1436 (Trodusquemine) |
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Applications |
Enzyme inhibition assay showed that MSI-1436 (Trodusquemine) inhibited PTP1B 200 times more in a dose-dependent manner than TCPTP (IC 50 = 1 umol/l vs. 224 umol/l). |
| Cell experiment [1]: | |
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Cell lines |
HepG2 cell line |
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Preparation Method |
Hep G2 cells were pretreated with 10 μmol/l MSI-1436 (Trodusquemine) or sodium orthovanadate for 10 min at 37 °C, then incubated with 10 mmol/l pNPP for 30 min at 37 °C. Samples of the supernatants were spectrophotometrically analyzed at OD405 for hydolyzed pNP, a direct end product of phosphatase activity. |
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Reaction Conditions |
10 µmol/l MSI-1436 (Trodusquemine) for 10 min at 37 °C |
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Applications |
Quantification of phosphatase activity measured in intact cell assays Incubation of intact HepG2 cells with 10 umol/l MSI-1436 (Trodusquemine) resulted in a 53% inhibition of phosphatase activity compared with control (no inhibitor). |
| Animal experiment [1]: | |
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Animal models |
Male AKR/J mice |
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Preparation Method |
Male AKR/J mice were randomly placed on ad libitum 10, 45, or 60% fat kcal diets.After 14 weeks, mice were randomly assigned to three treatment groups; MSI-1436 (Trodusquemine), vehicle, or pair-fed. PF animals were injected with saline and allotted the amount of food consumed daily by trodusquemine-treated animals. |
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Dosage form |
MSI-1436 (Trodusquemine)(initial dose of 10 mg/kg followed by intraperitoneal injection of 5 mg/kg 3 times weekly) for 23 days |
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Applications |
MSI-1436 (Trodusquemine)-treated animals demonstrated weight loss in a manner proportional to their pretreatment weights; heavier mice lost a greater overall percentage of BW. |
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References: [1].Lantz KA, Hart SG, et,al.Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity (Silver Spring). 2010 Aug;18(8):1516-23. doi: 10.1038/oby.2009.444. Epub 2010 Jan 14. PMID: 20075852. |
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| Cas No. | 186139-09-3 | SDF | |
| 别名 | Trodusquemine; Aminosterol-1436 | ||
| Canonical SMILES | NCCCNCCCCNCCCN[C@@H]1C[C@@](C[C@@H](O)[C@]2([H])[C@]3([H])CC[C@@]4(C)[C@@]2([H])CC[C@@]4([C@H](C)CC[C@@H](OS(=O)(O)=O)C(C)C)[H])([H])[C@]3(C)CC1 | ||
| 分子式 | C37H72N4O5S | 分子量 | 685.06 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.4597 mL | 7.2986 mL | 14.5973 mL |
| 5 mM | 0.2919 mL | 1.4597 mL | 2.9195 mL |
| 10 mM | 0.146 mL | 0.7299 mL | 1.4597 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
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Quality Control & SDS
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