客户使用产品发表文献 1 篇

Front Immunol 13 (2022): 1053856.PMID:36618415

质量管理

Related Biological Data

PTP1B, immune infiltration and CSCs index in cancers. (F) The cell inhibition rate of MSI-1436 (a PTP1B inhibitor) in different cancer cell lines with different doses. (G) Sensitivity effect of MSI-1436 and PD1 inhibitor (tislelizumab) in AML patient samples.
After incubating 48 h, the cytotoxicity of MSI-1436 (GLPBIO) was measured by adding 10μL cell counting kit-8 (CCK-8) at 450 nm.
Front Immunol 13 (2022): 1053856. PMID: 36618415 IF: 7.3

产品文档

Quality Control & SDS

View current batch:

Purity: >95.00%

实验参考方法

Kinase experiment [1]:
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.
Reaction Conditions	10 µmol/l MSI-1436 (Trodusquemine)
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]:
Cell lines	HepG2 cell line
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.
Reaction Conditions	10 µmol/l MSI-1436 (Trodusquemine) for 10 min at 37 °C
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]:
Animal models	Male AKR/J mice
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.
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
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.
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.

产品描述

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]。

Chemical Properties

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。
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。

溶解性数据

制备储备液
		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

摩尔浓度计算器
稀释计算器
分子量计算器

计算

动物体内配方计算器 (澄清溶液)

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，注：如该浓度超过该批次药物DMSO溶解度，请先联系GLPBIO）；

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。

注意：1. 首先保证母液是澄清的；
2. 一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。

Research Update

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.PMID:20075852DOI:10.1038/oby.2009.444.

Trodusquemine (MSI-1436) causes rapid and reversible weight loss in genetic models of obesity. To better predict the potential effects of Trodusquemine in the clinic, we investigated the effects of Trodusquemine treatment in a murine model of diet-induced obesity (DIO). Trodusquemine suppressed appetite, reduced body weight (BW) in a fat-specific manner, and improved plasma insulin and leptin levels in mice. Screening assays revealed that Trodusquemine selectively inhibited protein-tyrosine phosphatase 1B (PTP1B), a key enzyme regulating insulin and leptin signaling. Trodusquemine significantly enhanced insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) beta and STAT3, direct targets of PTP1B, in HepG2 cells in vitro and/or hypothalamic tissue in vivo. These data establish Trodusquemine as an effective central and peripheral PTP1B inhibitor with the potential to elicit noncachectic fat-specific weight loss and improve insulin and leptin levels.

MSI-1436 reduces acute food intake without affecting dopamine transporter activity

Pharmacol Biochem Behav 2010 Nov;97(1):138-43.PMID:20478327DOI:10.1016/j.pbb.2010.05.010.

Many therapies designed to reduce food intake and body weight act, in part, by blocking the dopamine transporter (DAT) - a protein responsible for clearing extracellular dopamine (DA) after release thereby terminating its action. Here, we found that a single injection of the drug Trodusquemine (MSI-1436) decreased food intake in rats. To assess the effects of MSI-1436 on DAT function, fast-scan cyclic voltammetry was used to measure DA concentration changes in the ventral striatum. DA release was evoked by electrical stimulation of the ventral tegmental area every 5 min. After 3 baseline measurements, rats were injected with MSI-1436 (10 mg/kg), the known DAT blocker bupropion (80 mg/kg) or saline and evoked DA release and reuptake were monitored for an additional hour. Neither saline nor MSI-1436 caused a significant change in the magnitude of evoked release from baseline values whereas bupropion caused a significant increase. In addition, neither saline nor MSI-1436 significantly increased DA decay rates while such an increase was observed with bupropion. Thus, over a time course when MSI-1436 suppresses food intake it does not affect DAT function. The results support MSI-1436 as an anti-obesity treatment which spares DAT.

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.PMID:33536069DOI:10.1186/s13287-020-02102-x.

Background: Protein tyrosine phosphatase 1B (PTP1B) is one of the major negative regulators of leptin and insulin signaling, and has been strongly implicated in insulin resistance development in the course of obesity and metabolic syndrome conditions; however, its exact role in controlling adipose tissue biogenesis is still poorly understood. Objectives: This investigation aimed to elucidate whether selective inhibition of PTP1B using MSI-1436 compound may improve and restore the defective adipogenicity of ASCs isolated from EMS-affected horses. Methods: Equine ASC EMS cells were cultured under adipogenic conditions in the presence of PTP1B inhibitor and were subsequently tested for expression of the main adipogenic-related genes using RT-qPCR, changes in free fatty acid profiles by means of GC-MS technique, and for mitochondrial dynamics improvement through the analysis of mitochondrial transmembrane potential and oxidative stress. Results: Selective inhibition of PTP1B in equine ASC EMS cells improved substantially adipogenic differentiation by promoting cellular proliferation and normalizing expression of C/EBPalpha, PPAR纬, and Adipoq markers that are critical for proper adipogenesis. Levels of secreted adiponectin and PPAR纬 were also shown to be increased in MSI-1436-conditioned cells, while total leptin levels markedly dropped under the same conditions. Moreover, MSI-1436 treatment enabled the regulation of metabolic-related transcripts that are crosslink to adipogenesis, namely Akt1, Akt2, and SHBG. The obtained results demonstrated also an obvious reduction in intracellular accumulated ROS and NO, as well as mitigated ER stress through the downregulation of Chop, Perk, Atf6, Ire1, and Xbp1 transcripts upon PTP1B inhibition. Furthermore, general fluctuations in FFA composition of all differentiated groups have been highlighted, where palmitic acid, palmitoleic acid, stearic acid, and linolelaidic acid that are known to be associated with the development of metabolic disorders were found to be normalized upon PTP1B inhibition during adipogenic differentiation. Conclusion: The presented data provides the evidence that the use of PTP1B inhibitor may be successful in controlling and enhancing adipogenic differentiation of impaired equine ASCs affected by metabolic syndrome, and thus offers new insights for the management of obesity through the regulation of adipose tissue dynamics.

Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound

Biochem Biophys Res Commun 2015 Feb 27;458(1):21-7.PMID:25623533DOI:10.1016/j.bbrc.2015.01.040.

Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) 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. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-尾 (IR尾), Akt and GSK3尾. Intraperitoneal administration of Claramine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. A single intraperitoneal dose of Claramine, like an equivalent dose of Trodusquemine, suppressed feeding and caused weight loss without increasing energy expenditure. In summary, Claramine is an alternative more easily manufactured compound for the treatment of type II diabetes.

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues

Int J Mol Sci 2022 Jan 19;23(3):1075.PMID:35162998DOI:10.3390/ijms23031075.

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, Trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

MSI-1436 (Trodusquemine)

Customer Reviews

B1