NAZ2329
目录号 : GC61621
NAZ2329是受体型蛋白质酪氨酸磷酸酶(RPTPs)R5亚家族的第一个细胞可渗透抑制剂，相对于其他PTPs，它变构且优先抑制PTPRZ(hPTPRZ1的IC50=7.5µM)和PTPRG(hPTPRGIC50=4.8µM)。NAZ2329与PTPRZ的D1结构域结合，相对于PTPRZ整个(D1+D2)片段，其更有效地抑制PTPRZ1-D1片段，其IC50为1.1µM。NAZ2329可有效抑制胶质母细胞瘤细胞的肿瘤生长并抑制干细胞样特性。
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
NAZ2329, the first cell-permeable inhibitor of R5 subfamily of receptor-type protein tyrosine phosphatases (RPTPs), allosterically and preferentially inhibits PTPRZ (IC50=7.5 µM for hPTPRZ1) and PTPRG (IC50=4.8 µM for hPTPRG) over other PTPs. NAZ2329 binds to the active D1 domain and more potently inhibits PTPRZ-D1 fragment (IC50 of 1.1 µM) than the whole intracellular (D1 + D2) fragment (IC50 of 7.5 µM). NAZ2329 can effectively inhibit tumor growth of the glioblastoma cells and suppress stem cell-like properties[1].
NAZ2329 (0-25 µM; 48 hours) dose-dependently inhibits cell proliferation and migration in all cell lines (rat glioblastoma cells bearing C6 clone and human U251 glioblastoma cells) [1].NAZ2329 (25 µM; 0-90 min) obviously promotes the phosphorylation level of paxillin at Tyr-118 site, leading to inhibition for PTPR substrate[1]. Cell Proliferation Assay[1] Cell Line: Rat glioblastoma cells bearing C6 clone, human U251 glioblastoma cells
NAZ2329 (22.5 mg/kg; intraperitoneal injection; twice per week; 40 days) alone has a moderate inhibitory effect. However, the combination of Temozolomide and NAZ2329 exerts a significantly increased inhibition of tumor growth compared with the control group, the NAZ2329 monotherapy group and the Temozolomide monotherapy group[1]. Animal Model: Female BALB/c- nu/nu mice aged 4 week-old bearing parental or Ptprz-knockdown C6 cells[1]
[1]. Akihiro Fujikawa, et al. Targeting PTPRZ inhibits stem cell-like properties and tumorigenicity in glioblastoma cells. Sci Rep. 2017 Jul 17;7(1):5609.
| Cas No. | SDF | ||
| Canonical SMILES | CCOC1=C(CSC2=C(C(NS(=O)(C3=CC=CC=C3)=O)=O)SC=C2)C=C(C(F)(F)F)C=C1 | ||
| 分子式 | C21H18F3NO4S3 | 分子量 | 501.56 |
| 溶解度 | DMSO: 100 mg/mL (199.38 mM) | 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 | 1.9938 mL | 9.9689 mL | 19.9378 mL |
| 5 mM | 0.3988 mL | 1.9938 mL | 3.9876 mL |
| 10 mM | 0.1994 mL | 0.9969 mL | 1.9938 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。
Allosteric inhibition induces an open WPD-loop: a new avenue towards glioblastoma therapy
RSC Adv 2018 Nov 30;8(70):40187-40197.PMID:35558220DOI:10.1039/c8ra08427k.
The mobility of loops around the catalytic site of a protein remains crucial to its activity. Dynamics of the WPD-loop is an essential determinant of the catalytic activity of tyrosine-protein phosphatase zeta, an implicated protein in glioblastoma cells. The WPD-loop assumes a closed conformation upon substrate binding in order to position its catalytic aspartate to participate in catalysis. Herein, we explore the impact of NAZ2329, a recently identified allosteric inhibitor of tyrosine-protein phosphatase zeta, on the atomic flexibility of the WPD-loop. The druglikeness of NAZ2329 was assessed using the SwissADME online tool. The enzymatic complex was then subjected to conformational simulations using the AMBER molecular dynamics software. Structural analysis revealed that NAZ2329 induced an open conformation of the crucial WPD-loop, consequently impeding enzyme activity even upon substrate binding. Based on the molecular interactions between NAZ2329 and tyrosine-protein phosphatase zeta, a pharmacophore model was generated to exhibit the important functional moieties of NAZ2329. These findings provide an insightful molecular and structural mechanism in targeting tyrosine-protein phosphatase zeta as a therapeutic intervention for glioblastoma. We believe that this optimized pharmacophoric model will aid in the design of improved anti-tyrosine phosphatase agents, thus allowing for increased patient adherence.
Targeting PTPRZ inhibits stem cell-like properties and tumorigenicity in glioblastoma cells
Sci Rep 2017 Jul 17;7(1):5609.PMID:28717188DOI:10.1038/s41598-017-05931-8.
The R5 subfamily of receptor-type protein tyrosine phosphatases (RPTPs) comprises PTPRZ and PTPRG. A recent study on primary human glioblastomas suggested a close association between PTPRZ1 (human PTPRZ) expression and cancer stemness. However, the functional roles of PTPRZ activity in glioma stem cells have remained unclear. In the present study, we found that sphere-forming cells from the rat C6 and human U251 glioblastoma cell lines showed high expression levels of PTPRZ-B, the short receptor isoform of PTPRZ. Stable PTPRZ knockdown altered the expression levels of stem cell transcription factors such as SOX2, OLIG2, and POU3F2 and decreased the sphere-forming abilities of these cells. Suppressive effects on the cancer stem-like properties of the cells were also observed following the knockdown of PTPRG. Here, we identified NAZ2329, a cell-permeable small molecule that allosterically inhibits both PTPRZ and PTPRG. NAZ2329 reduced the expression of SOX2 in C6 and U251 cells and abrogated the sphere-forming abilities of these cells. Tumor growth in the C6 xenograft mouse model was significantly slower with the co-treatment of NAZ2329 with temozolomide, an alkylating agent, than with the individual treatments. These results indicate that pharmacological inhibition of R5 RPTPs is a promising strategy for the treatment of malignant gliomas.
A head-to-toe dimerization has physiological relevance for ligand-induced inactivation of protein tyrosine receptor type Z
J Biol Chem 2019 Oct 11;294(41):14953-14965.PMID:31416834DOI:10.1074/jbc.RA119.007878.
Protein-tyrosine phosphatase (PTPase) receptor type Z (PTPRZ) has two receptor isoforms, PTPRZ-A and -B, containing tandem intracellular PTP-D1 and -D2 domains, with only D1 being active. Pleiotrophin (PTN) binding to the extracellular PTPRZ region leads to inactivation of its PTPase activity, thereby facilitating oligodendrocyte precursor cell (OPC) differentiation and myelination in the central nervous system. However, the mechanisms responsible for PTN-induced PTPRZ inactivation remain unclear. We herein report that the crystal structure of the intracellular region of PTPRZ (PTPRZ-ICR) shows a "head-to-toe"-type dimer conformation, with D2 masking the catalytic site of D1. MS analyses revealed that PTPRZ-ICR proteins remain in monomer-dimer equilibrium in aqueous solution and that a substrate-derived inhibitory peptide or competitive inhibitor (SCB4380) specifically bind to the monomer form in a 1:1 ratio. A D2 deletion (ΔD2) or dimer interface mutation (DDKK) disrupted dimer formation, but SCB4380 binding was maintained. Similar to WT PTPRZ-B, monomer-biased PTPRZ-B-ΔD2 and PTPRZ-B-DDKK variants efficiently dephosphorylated p190RhoGAP at Tyr-1105 when co-expressed in BHK-21 cells. The catalytic activities of these variants were not suppressed by PTN treatment, but were inhibited by the cell-permeable PTPase inhibitor NAZ2329. Of note, the PTN treatment did not enhance OPC differentiation in primary cultured glial cells from ΔD2 or PTPase-inactive PTPRZ-B (CS) mutant knock-in mice. Our results thus indicate that PTN-induced PTPRZ inactivation results from dimer formation of the intracellular tandem PTP domains in a head-to-toe configuration, which is physiologically relevant to the control of OPC differentiation in vivo.