ZZW-115
目录号 : GC61392
A NUPR1 inhibitor
Cas No.:801991-87-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ZZW-115 is an inhibitor of nuclear protein 1 (NUPR1).1 It binds to NUPR1 (Kd = 2.1 ?M) in a cell-free assay. ZZW-115 is cytotoxic against a panel of 11 pancreatic ductal adenocarcinoma cell lines (IC50s = 0.84-4.93 ?M), as well as against a panel of 16 additional cancer cell lines, including glioblastoma, lymphoma, and leukemia cells (IC50s =0.25-7.75 ?M). It induces apoptosis and necrosis in MiaPaCa-2, LIPC, Foie8b, 02-063, and HN14 pancreatic cancer cells when used at concentrations of 3 and 5 ?M. ZZW-115 induces accumulation of reactive oxygen species (ROS), lipid peroxidation, and ferroptosis in MiaPaCa-2 cells in a concentration-dependent manner.2 It reduces tumor growth in a MiaPaCa-2 mouse xenograft model when administered at doses of 1, 2.5, or 5 mg/kg.1
1.Santofimia-Casta?o, P., Xia, Y., Lan, W., et al.Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosisJ. Clin. Invest.129(6)2500-2513(2019) 2.Huang, C., Santofimia-Casta?o, P., Liu, X., et al.NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent mannerCell Death Discov.7(1)269(2021)
| Cas No. | 801991-87-7 | SDF | |
| Canonical SMILES | FC(C(C=C1N2CCCN3CCN(CCN(C)C)CC3)=CC=C1SC4=C2C=CC=C4)(F)F | ||
| 分子式 | C24H31F3N4S | 分子量 | 464.59 |
| 溶解度 | 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 | 2.1524 mL | 10.7622 mL | 21.5244 mL |
| 5 mM | 0.4305 mL | 2.1524 mL | 4.3049 mL |
| 10 mM | 0.2152 mL | 1.0762 mL | 2.1524 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。
NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner
Cell Death Discov 2021 Oct 1;7(1):269.PMID:34599149DOI:10.1038/s41420-021-00662-2.
Ferroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents. The ferroptotic activity can be improved by inhibiting antioxidant factors in pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells. In addition, ZZW-115-treatment increases the accumulation of hydroperoxided lipids in these cells. We also found that a loss of activity and strong deregulation of key enzymes involved in the GSH- and GPX-dependent antioxidant systems upon ZZW-115 treatment. These results have been validated in xenografts induced with PDAC- and HCC-derived cells in nude mice during the treatment with ZZW-115. More importantly, we demonstrate that ZZW-115-induced mitochondrial morphological changes, compatible with the ferroptotic process, as well as mitochondrial network disorganization and strong mitochondrial metabolic dysfunction, which are rescued by both Fer-1 and N-acetylcysteine (NAC). Of note, the expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. Altogether, these results demonstrate that the mitochondrial cell death mediated by NUPR1 inhibitor ZZW-115 is fully rescued by Fer-1 but also via TFAM complementation. In conclusion, TFAM could be considered as an antagonist of the ferroptotic cell death.
NUPR1 is a critical repressor of ferroptosis
Nat Commun 2021 Jan 28;12(1):647.PMID:33510144DOI:10.1038/s41467-021-20904-2.
Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in ferroptosis, although the key regulator for ferroptosis in iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, a stress-inducible transcription factor, as a driver of ferroptosis resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic cell death through diminishing iron accumulation and subsequent oxidative damage. Consequently, LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, whereas transfection-enforced re-expression of LCN2 restores resistance to ferroptosis in NUPR1-deficient cells. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn2 conditional knockout mice, or the small molecule ZZW-115) increases the activity of the ferroptosis inducer erastin and worsens pancreatitis, in suitable mouse models. These findings suggest a link between NUPR1-regulated iron metabolism and ferroptosis susceptibility.
ZZW-115-dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents
JCI Insight 2020 Sep 17;5(18):e138117.PMID:32780723DOI:10.1172/jci.insight.138117.
Establishing the interactome of the cancer-associated stress protein Nuclear Protein 1 (NUPR1), we found that it binds to several hundreds of proteins, including proteins involved in nuclear translocation, DNA repair, and key factors of the SUMO pathway. We demonstrated that the NUPR1 inhibitor ZZW-115, an organic synthetic molecule, competes with importins for the binding to the NLS region of NUPR1, thereby inhibiting its nuclear translocation. We hypothesized, and then proved, that inhibition of NUPR1 by ZZW-115 sensitizes cancer cells to DNA damage induced by several genotoxic agents. Strikingly, we found that treatment with ZZW-115 reduced SUMOylation of several proteins involved in DNA damage response (DDR). We further report that the presence of recombinant NUPR1 improved the SUMOylation in a cell-free system, indicating that NUPR1 directly stimulates the SUMOylation machinery. We propose that ZZW-115 sensitizes cancer cells to genotoxic agents by inhibiting the nuclear translocation of NUPR1 and thereby decreasing the SUMOylation-dependent functions of key proteins involved in the DDR.
Targeting NUPR1 with the small compound ZZW-115 is an efficient strategy to treat hepatocellular carcinoma
Cancer Lett 2020 Aug 28;486:8-17.PMID:32446862DOI:10.1016/j.canlet.2020.04.024.
HCC is a highly lethal malignancy with Sorafenib as the only molecularly targeted drug. The multifunctional stress-associated protein, NUPR1, plays an essential role in controlling cell growth, migration, invasion and Sorafenib resistance in HCC. We report here that NUPR1 expression is absent in healthy liver and it is progressively upregulated in HCC premalignant lesions such as hepatitis and cirrhosis with a maximum expression in HCC samples, highlighting that NUPR1 is a potential drug target for HCC. We therefore assessed in this work, ZZW-115, a strong inhibitor of NUPR1, as a promising candidate for the treatment of HCC. We validated its extraordinary antitumor effect on HCC by using two HCC cell lines, HepG2-and Hep3B, both in cell based experiments and xenografted mice. We further revealed that ZZW-115 treatment induced cell death by apoptosis and necroptosis mechanisms, with a concomitant mitochondrial metabolism failure that triggers lower ATP production. Furthermore, the ATP depletion cannot be rescued by the apoptosis inhibitor Z-VAD-FMK and/or the necrosis inhibitor Necrostatin-1, indicating that ZZW-115 induces cell death through the mitochondrial failure.
NUPR1 protects against hyperPARylation-dependent cell death
Commun Biol 2022 Jul 22;5(1):732.PMID:35869257DOI:10.1038/s42003-022-03705-1.
Proteomic, cellular and biochemical analysis of the stress protein NUPR1 reveals that it binds to PARP1 into the nucleus and inhibits PARP1 activity in vitro. Mutations on residues Ala33 or Thr68 of NUPR1 or treatment with its inhibitor ZZW-115 inhibits this effect. PARylation induced by 5-fluorouracil (5-FU) treatment is strongly enhanced by ZZW-115 and associated with a decrease of NAD+/NADH ratio and rescued by the PARP inhibitor olaparib. Cell death induced by ZZW-115 treatment of pancreas cancer-derived cells is rescued by olaparib and improved with PARG inhibitor PDD00017273. The mitochondrial catastrophe induced by ZZW-115 treatment or by genetic inactivation of NUPR1 is associated to a hyperPARylation of the mitochondria, disorganization of the mitochondrial network, mitochondrial membrane potential decrease, and with increase of superoxide production, intracellular level of reactive oxygen species (ROS) and cytosolic levels of Ca2+. These features are rescued by olaparib or NAD+ precursor nicotinamide mononucleotide in a dose-dependent manner and partially by antioxidants treatments. In conclusion, inactivation of NUPR1 induces a hyperPARylation, which in turn, induces a mitochondrial catastrophe and consequently a cell death through a non-canonical Parthanatos, since apoptosis inducing-factor (AIF) is not translocated out of the mitochondria.