PHPS1
(Synonyms: PTP Inhibitor V) 目录号 : GC44637A selective SHP-2 inhibitor
Cas No.:314291-83-3
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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- Datasheet
PHPS1 is a cell-permeable, phosphotyrosine mimetic that inhibits the Src homology region 2 domain-containing phosphatase (SHP)-2 (IC50 = 2.1 µ Ki = 0.73 µM). It is selective for SHP-2, inhibiting ECPTP, PTP1B, SHP-1, and mycobacterium MptpA at relatively higher concentrations (IC50s = 5.4, 19, 30, and 39 µM, respectively). PHPS1 has been shown to inhibit SHP-2-dependent cellular signaling and tumor cell colony formation.
Reference:
[1]. Hellmuth, K., Grosskopf, S., Lum, C.T., et al. Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking. Proceedings of the National Academy of Sciences of the United States of America 105(20), 7275-7280 (2008).
| Cas No. | 314291-83-3 | SDF | |
| 别名 | PTP Inhibitor V | ||
| 化学名 | 4-[2-[1,5-dihydro-3-(4-nitrophenyl)-5-oxo-1-phenyl-4H-pyrazol-4-ylidene]hydrazinyl]-benzenesulfonic acid | ||
| Canonical SMILES | O=C1N(C2=CC=CC=C2)N=C(C3=CC=C([N+]([O-])=O)C=C3)/C1=N\NC4=CC=C(S(O)(=O)=O)C=C4 | ||
| 分子式 | C21H15N5O6S | 分子量 | 465.4 |
| 溶解度 | 5mg/mL in DMSO, or in DMF | 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 | 2.1487 mL | 10.7434 mL | 21.4869 mL |
| 5 mM | 0.4297 mL | 2.1487 mL | 4.2974 mL |
| 10 mM | 0.2149 mL | 1.0743 mL | 2.1487 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.
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。
SHP2 inhibitor PHPS1 protects against atherosclerosis by inhibiting smooth muscle cell proliferation
BMC Cardiovasc Disord 2018 Apr 27;18(1):72.PMID:29703160DOI:10.1186/s12872-018-0816-2.
Background: Smooth muscle cells play an important role in the development of atherosclerosis. SHP2 is known to regulate the proliferation and migration of smooth muscle cells. The purpose of this study was to determine whether the SHP2 inhibitor PHPS1 has a pro-atherosclerotic or an atheroprotective effect in vivo and in vitro. Methods: After exposure to a high-cholesterol diet for 4 weeks, LDL receptor-deficient (Ldlr-/-) mice were exposed to the SHP2 inhibitor PHPS1 or vehicle. Body weight, serum glucose and lipid levels were determined. The size and composition of atherosclerotic plaques were measured by en face analysis, Movat staining and immunohistochemistry. The phosphorylation of SHP2 and related signaling molecules was analyzed by Western blot. Mechanistic analyses were performed in oxLDL-stimulated cultured vascular smooth muscle cells (VSMCs) with or without 10 mM PHPS1 pretreatment. Protein phosphorylation levels were detected by Western blot, and VSMC proliferation was assessed by BrdU staining. Results: PHPS1 decreased the number of atherosclerotic plaques without significantly affecting body weight, serum glucose levels or lipid metabolism. Plaque composition analysis showed a significant decrease in the number of VSMCs in atherosclerotic lesions of Ldlr-/- mice treated with PHPS1. Stimulation with oxLDL induced a dose-dependent increase in the number of VSMCs and in SHP2 and ERK phosphorylation levels, and these effects were blocked by PHPS1. Conclusion: The SHP2 inhibitor PHPS1 exerts a protective effect against atherosclerosis by reducing VSMC proliferation via SHP2/ERK pathway activation.
Overcoming interferon (IFN)-γ resistance ameliorates transforming growth factor (TGF)-β-mediated lung fibroblast-to-myofibroblast transition and bleomycin-induced pulmonary fibrosis
Biochem Pharmacol 2021 Jan;183:114356.PMID:33285108DOI:10.1016/j.bcp.2020.114356.
Abnormal activation of transforming growth factor (TGF)-β is a common cause of fibroblast activation and fibrosis. In bleomycin (BLM)-induced lung fibrosis, the marked expression of phospho-Src homology-2 domain-containing phosphatase (SHP) 2, phospho-signal transducer and activator of transcription (STAT) 3, and suppressor of cytokine signaling (SOCS) 3 was highly associated with pulmonary parenchymal lesions and collagen deposition. Human pulmonary fibroblasts differentiated into myofibroblasts exhibited activation of SHP2, SOCS3, protein inhibitor of activated STAT1, STAT3, interleukin (IL)-6, and IL-10. The significant retardation of interferon (IFN)-γ signaling in myofibroblasts was revealed by the decreased expression of phospho-STAT1, IFN-γ-associated genes, and IFN-γ-inducible protein (IP) 10. Microarray analysis showed an induction of fibrotic genes in TGF-β1-differentiated myofibroblasts, whereas IFN-γ-regulated anti-fibrotic genes were suppressed. Interestingly, BIBF 1120 treatment effectively inhibited both STAT3 and SHP2 phosphorylation in TGF-β1-differentiated myofibroblasts and BLM fibrotic lung tissues, which was accompanied by suppression of fibroblast-myofibroblast transition. Moreover, the combined treatment of BIBF 1120 plus IFN-γ or SHP2 inhibitor PHPS1 plus IFN-γ markedly reduced TGF-β1-induced α-smooth muscle actin and further ameliorated BLM lung fibrosis. Accordingly, myofibroblasts were hyporesponsiveness to IFN-γ, while blockade of SHP2 contributed to the anti-fibrotic efficacy of IFN-γ.
SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model
Mol Med 2020 Sep 21;26(1):89.PMID:32957908DOI:10.1186/s10020-020-00210-1.
Background: Hypovolemic shock and septic challenge are two major causes of acute kidney injury (AKI) in the clinic setting. Src homology 2 domain-containing phosphatase 2 (SHP2) is one of the major protein phosphatase tyrosine phosphatase (PTPs), which play a significant role in maintaining immunological homeostasis by regulating many facets of immune cell signaling. In this study, we explored whether SHP2 signaling contributed to development of AKI sequential hemorrhage (Hem) and cecal ligation and puncture (CLP) and whether inactivation of SHP2 through administration of its selective inhibitor, phenylhydrazonopyrazolone sulfonate 1 (PHPS1), attenuated this injury. Methods: Male C57BL/6 mice were subjected to Hem (a "priming" insult) followed by CLP or sham-Hem plus sham-CLP (S/S) as controls. Samples of blood and kidney were harvested at 24 h post CLP. The expression of neutrophil gelatinase-associated lipocalin (NGAL), high mobility group box 1 (HMGB1), caspase3 as well as SHP2:phospho-SHP2, extracellular-regulated kinase (Erk1/2): phospho-Erk1/2, and signal transducer and activator of transcription 3 (STAT3):phospho-STAT3 protein in kidney tissues were detected by Western blotting. The levels of creatinine (Cre) and blood urea nitrogen (BUN) in serum were measured according to the manufacturer's instructions. Blood inflammatory cytokine/chemokine levels were detected by ELISA. Results: We found that indices of kidney injury, including levels of BUN, Cre and NGAL as well as histopathologic changes, were significantly increased after Hem/CLP in comparison with that in the S/S group. Furthermore, Hem/CLP resulted in elevated serum levels of inflammatory cytokines/chemokines, and induced increased levels of HMGB1, SHP2:phospho-SHP2, Erk1/2:phospho-Erk1/2, and STAT3:phospho-STAT3 protein expression in the kidney. Treatment with PHPS1 markedly attenuated these Hem/CLP-induced changes. Conclusions: In conclusion, our data indicate that SHP2 inhibition attenuates AKI induced by our double-hit/sequential insult model of Hem/CLP and that this protective action may be attributable to its ability to mitigate activation of the Erk1/2 and STAT3 signaling pathway. We believe this is a potentially important finding with clinical implications warranting further investigation.
SH2 domain-containing protein tyrosine phosphatase-2 (SHP-2) prevents cardiac remodeling after myocardial infarction through ERK/SMAD signaling pathway
Hum Cell 2021 Mar;34(2):325-334.PMID:33415691DOI:10.1007/s13577-020-00430-x.
In this study, we aimed to investigate the role of SH2 domain-containing protein tyrosine phosphatase-2 (SHP-2) in cardiac remodeling after myocardial infarction (MI) and explore the underlying molecular mechanism. MI model was established by ligation of the left anterior descending coronary artery. C57/BL6J mice were randomly administered with 3.0 mg/kg/day PHPS1 (PHPS1-treated group) or normal saline (model group) by intraperitoneal injection. After 4 weeks of infusion, the effects of PHPS1 on cardiac remodeling were evaluated. Echocardiography results showed that PHPS1 treatment aggravated the MI-induced deterioration of cardiac function, with worse cardiac function parameters. PHPS1 treatment significantly increased the infarcted area, as well as the fibrotic area and the expression of collagen I and collagen III. Western blots and immunofluorescence staining showed that PHPS1 treatment up-regulated the expression of p-GRK2, p-SMAD2/3 and p-ERK1/2, while U0126 reversed the effect of PHPS1. The present study indicated that PHPS1 treatment contributed to myocardial fibrosis and infarction by activating ERK/SMAD signaling pathway, suggesting that SHP-2 may be a promising treatment target for cardiac remodeling after MI.
Molecular characterization and interstrain variability of PHPS1, a plasmid isolated from the Sydney strain (SS1) of Helicobacter pylori
Plasmid 1999 Mar;41(2):97-109.PMID:10087213DOI:10.1006/plas.1998.1383.
The 5846-bp circular plasmid PHPS1 of Helicobacter pylori Sydney strain, SS1, was cloned, sequenced, and structurally characterized. The SS1 strain is widely used in animal studies of H. pylori infection. The sequence of PHPS1 revealed three open reading frames (ORFs), all of which are transcribed. Two ORFs encode putative plasmid replication proteins, RepA and RepB, similar to replicases resident on theta plasmids. In contrast, the function of ORF2 remains cryptic due to the absence of sequence similarity with any known protein in sequence databases. In addition, species specificity of these three coding regions was shown using DNA dot blot hybridization in 57 diverse clinical H. pylori isolates and 32 Helicobacter and Campylobacter strains. RepA appears to be the predominant plasmid replication protein of H. pylori and the deduced amino acid sequence was highly conserved (76-96%) in 8 H. pylori isolates, including SS1. RepB was detected in 3 H. pylori isolates examined in this study, 2 of which possess only the repB gene. Analysis of the protein sequences of these two replicases, together with previously characterized H. pylori plasmid replication proteins, supports the formation of a distinct class of H. pylori plasmid proteins. Moreover, comprehensive analysis of the whole genome sequence of H. pylori strain 26695, PHPS1, and other H. pylori plasmid sequences that are available revealed interesting insights as to the occurrence of plasmid-mediated recombination within H. pylori. Common regions between plasmids and chromosome sequences of H. pylori were identified in this study which could only have arisen by genetic recombination, thus providing the first line of evidence, albeit indirectly, of the contribution of H. pylori plasmids in generating an extensive genetic heterogeneity characteristic of this important gastroduodenal pathogen.