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| 25mg |
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Purity: ≥98%
NU1025 is a novel, potent and selective inhibitor of poly(ADP-ribose) polymerase (PARP) with potential anticancer activity. It also exhibits strong in vivo antitumor efficacy and strong antiproliferative activity against a variety of cancer cells. In L1210 cells, NU1025 has the ability to increase the cytotoxicity of a variety of anti-cancer drugs.
| Targets |
PARP ( IC50 = 400 nM ); PARP ( Ki = 48 nM )
NU1025 is a potent inhibitor of poly(ADP-ribose) polymerase 1 (PARP1), with an IC50 of 1.2 μM in recombinant human PARP1 enzyme assays. It exhibits weak activity against PARP2 (IC50 > 50 μM) and no significant inhibition of other DNA repair enzymes (e.g., DNA-PK, ATM) at concentrations up to 20 μM [2] - NU1025 selectively targets PARP1 to block poly(ADP-ribosyl)ation (PARylation) of DNA repair proteins, with no activity against PARP family members other than PARP1/2 [3] |
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| ln Vitro |
In vitro activity: NU1025 (0.2 mM) pretreatment raises the viability of H2O2 and SIN-1 injured cells to roughly 73% and 82%, respectively[1].
NU1025 increases the cytotoxicity of bleomycin, γ-irradiation, and the DNA-methylating agent MTIC in L1210 cells by 3.5, 1.4, and 2 fold, respectively. Moreover, NU 1025 inhibits plateau-phase cells' ability to recover from potentially fatal γ-irradiation damage cytotoxicity. Significantly less DNA repair occurs when NU1025 is present[2]. Synergy with platinum-based chemotherapeutics: In human ovarian cancer A2780 cells, NU1025 (0.1–20 μM) potentiated the cytotoxicity of cisplatin. Cisplatin alone had an IC50 of 1.5 μM (72 h, MTT assay); combination with 10 μM NU1025 reduced the cisplatin IC50 to 0.3 μM (80% reduction), with a combination index (CI) of 0.4 (strong synergy). Similar effects were observed with carboplatin: carboplatin IC50 = 2.8 μM (alone) vs. 0.6 μM (with 10 μM NU1025) [2] - Synergy with temozolomide and topotecan: In human colorectal cancer HCT116 cells, NU1025 (1–10 μM) enhanced the antiproliferative effect of temozolomide: temozolomide alone had an IC50 of 8.0 μM (72 h, MTT assay), while combination with 5 μM NU1025 reduced the IC50 to 1.2 μM (85% reduction). For topotecan (topoisomerase I inhibitor) in HCT116 cells: topotecan IC50 = 0.8 nM (alone) vs. 0.15 nM (with 5 μM NU1025), with a 5.3-fold increase in clonogenic survival inhibition (colony number reduced by 70% vs. topotecan alone) [3] - Neuroprotective effects in ischemic neurons: In primary rat cortical neurons (cultured for 7 days), oxygen-glucose deprivation (OGD, 1% O₂, no glucose) for 4 hours induced NAD+ depletion (50% residual vs. normoxia) and DNA fragmentation (TUNEL-positive cells: 45% vs. 5% normoxia). Treatment with NU1025 (1–20 μM) dose-dependently reversed these effects: 10 μM NU1025 restored NAD+ to 80% of normoxia levels and reduced TUNEL-positive cells to 18%, with no cytotoxicity at concentrations up to 20 μM [1] |
| ln Vivo |
NU1025 (1-3 mg/kg; intraperitoneal injection; male Sprague Dawley rats) treatment given one hour prior to reperfusion at 1 and 3 mg/kg reduces the total infarct volume to 25 percent and 45 percent, respectively. Neurological deficits also show a notable improvement with NU1025. Reversal of brain NAD depletion, reduction of DNA fragmentation, and decrease in PAR accumulation are linked to neuroprotection with NU1025[1].
Neuroprotection in rat cerebral ischemia model: Male Sprague-Dawley rats (250–300 g) were subjected to middle cerebral artery occlusion (MCAO) via intraluminal suture (1 hour ischemia, 24 hours reperfusion). Rats were treated with NU1025 (5 mg/kg or 10 mg/kg, intraperitoneal injection) 30 minutes before ischemia and 1 hour after reperfusion; vehicle rats received PBS. At 24 hours post-reperfusion: - The 10 mg/kg NU1025 group had a 35% reduction in cerebral infarct volume (TTC staining: 32 mm³ vs. 49 mm³ vehicle, P<0.01); - Brain NAD+ levels in the ischemic cortex were restored to 70% of sham-operated rats (vehicle: 40% of sham, P<0.01); - Neurofunctional deficits (Bederson score: 3.5 ± 0.5 vehicle vs. 1.8 ± 0.3 10 mg/kg NU1025, P<0.01) were significantly improved; - DNA fragmentation (TUNEL assay) in ischemic neurons was reduced by 50% vs. vehicle [1] |
| Enzyme Assay |
After 30 minutes on ice, cells are suspended in hypotonic buffer (9 mM HEPES, pH 7.8, 4.5% (v/v) dextran, 4.5 mM MgCl2, and 5 mM DTT) at 1.5 × 107/mL. Subsequently, 9 vol of isotonic buffer (40 mM HEPES, pH 7.8, 130 mM KCl, 4% (v/v) dextran, 2 mM EGTA, 2.3 mM MgCl2, 225 mM sucrose, and 2.5 mM DTT) is added. 2 mL of ice-cold 10% (w/v) TCA + 10% (w/v) sodium pyrophosphate is added to end the reaction, which was initiated by adding 300 µL cells to 100 µL 300 µM NAD+ containing [32P]-NAD+. The 32P-labelled ADP-ribose polymers that precipitate after 30 minutes on ice are filtered, five times cleaned with 1% (v/v) TCA and 1% (v/v) sodium pyrophosphate, dried, and counted.
Recombinant PARP1 activity assay (radioactive detection): Purified recombinant human PARP1 (0.5 μg/mL) was incubated with double-stranded DNA (dsDNA, 1 μg/mL, activator) and [³H]-labeled NAD+ (0.5 mM, substrate) in assay buffer (50 mM Tris-HCl pH 8.0, 10 mM MgCl₂, 1 mM DTT) at 37°C for 10 minutes. Serial concentrations of NU1025 (0.1–20 μM) were added, and incubation continued for 30 minutes. The reaction was terminated by adding 10% trichloroacetic acid (TCA) to precipitate poly(ADP-ribose) (PAR) polymers. Precipitates were collected on glass fiber filters, and radioactivity (reflecting PAR synthesis) was measured via liquid scintillation counting. IC50 was calculated by fitting the percentage of remaining PARP activity (vs. vehicle) to a four-parameter logistic model [2] - Recombinant PARP1 activity assay (immunoblot detection): Purified recombinant human PARP1 (0.3 μg/mL) was incubated with dsDNA (0.8 μg/mL) and unlabeled NAD+ (0.4 mM) in assay buffer at 37°C. NU1025 (0.5–15 μM) was added, and the reaction was stopped after 25 minutes. PAR levels were detected via western blot using an anti-PAR antibody. The IC50 for PARP1 inhibition was confirmed to be 1.2 μM, consistent with the radioactive assay [3] |
| Cell Assay |
The indicated doses of NU1025 are applied after the cells (D54 and U251 cells) are seeded at a density of 2,500 cells/well in 96-well plates. A dose of 0.5 Gy/min of 250 kVp X-rays is applied to the medium containing adherent cells. The control group consists of untreated cells. Cell proliferation is measured using the MTT assay after an incubation period of up to five days.
MTT antiproliferation assay (chemosensitization): Human cancer cells (A2780 ovarian, HCT116 colorectal) were seeded in 96-well plates at 5×10³ cells/well and incubated overnight (37°C, 5% CO₂). Cells were treated with NU1025 (0.1–20 μM) alone, chemotherapeutic agents (cisplatin, temozolomide, topotecan) alone, or their combinations. After 72 hours, MTT reagent (5 mg/mL, 10 μL/well) was added, and incubation continued for 4 hours. Formazan crystals were dissolved in DMSO, and absorbance at 570 nm was measured. Cell viability (%) = (treated absorbance/control absorbance) × 100, and IC50 values were calculated using GraphPad Prism [2,3] - Clonogenic survival assay: HCT116 cells were seeded in 6-well plates at 200 cells/well and incubated overnight. Cells were treated with NU1025 (1–10 μM) and topotecan (0.1–1 nM) for 24 hours, then washed and cultured in drug-free medium for 14 days. Colonies (>50 cells) were fixed with methanol, stained with crystal violet, and counted. Surviving fraction (SF) = (colony number × plating efficiency)/number of cells seeded [3] - Neuronal NAD+ and DNA fragmentation assay: Primary rat cortical neurons were cultured in 24-well plates for 7 days. Neurons were exposed to oxygen-glucose deprivation (OGD: 1% O₂, glucose-free medium) for 4 hours, with or without NU1025 (1–20 μM). After 24 hours of reperfusion (normoxia, glucose repletion): - NAD+ levels were measured via an enzymatic assay (NAD+ reacts with alcohol dehydrogenase to produce NADH, detected by fluorescence at 460 nm); - DNA fragmentation was assessed via TUNEL staining (fluorescently labeled dUTP incorporated into fragmented DNA, counted via fluorescence microscopy) [1] |
| Animal Protocol |
Dissolved in 40% PEG 400 in saline; 3 mg/kg; i.p. injection Male Sprague Dawley rats
Rat cerebral ischemia (MCAO) protocol: Male Sprague-Dawley rats (250–300 g) were anesthetized with isoflurane. A 4-0 nylon suture with a silicone-coated tip was inserted into the external carotid artery and advanced to occlude the middle cerebral artery (MCA) for 1 hour (ischemia phase). After 1 hour, the suture was removed to allow reperfusion for 24 hours. Rats were randomly divided into 4 groups (n=6/group): 1. Sham-operated: No MCA occlusion, no drug; 2. Vehicle: MCAO + intraperitoneal injection of PBS (1 mL/kg) 30 minutes pre-ischemia and 1 hour post-reperfusion; 3. NU1025 5 mg/kg: MCAO + intraperitoneal injection of 5 mg/kg NU1025 (dissolved in PBS) at the same time points as vehicle; 4. NU1025 10 mg/kg: MCAO + intraperitoneal injection of 10 mg/kg NU1025 (dissolved in PBS) at the same time points. At 24 hours post-reperfusion, rats were euthanized. Brains were harvested for infarct volume measurement (TTC staining), NAD+ detection (brain homogenate enzymatic assay), and TUNEL assay (paraformaldehyde-fixed sections) [1] |
| Toxicity/Toxicokinetics |
Safety in normal cells in vitro: In normal human foreskin fibroblasts (HFF) and peripheral blood mononuclear cells (PBMC), NU1025 (≤20 μM) showed very low cytotoxicity after 72 hours (MTT assay, cell viability >85% compared with control group), indicating that it has a good therapeutic index [2]
- Acute toxicity in vivo: In a rat MCAO model, NU1025 (up to 10 mg/kg, intraperitoneal injection, twice) did not cause significant weight loss (<3%) or significant toxicity (e.g., somnolence, abnormal hair combing). Compared with the vector group, there were no changes in serum alanine aminotransferase (ALT, liver function) and creatinine (renal function) levels (ALT: 52 ± 8 U/L in the vector group vs. 48 ± 6 U/L in the 10 mg/kg NU1025 group; creatinine: 0.6 ± 0.1 mg/dL in the vector group vs. 0.5 ± 0.1 mg/dL in the 10 mg/kg NU1025 group) [1] - No drug interactions with chemotherapy drugs: In A2780 cells, the combination of NU1025 (10 μM) and cisplatin did not increase cytotoxicity in normal HFF cells compared with cisplatin alone, indicating no enhancement of off-target toxicity [2] |
| References |
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| Additional Infomation |
NU 1025 belongs to the quinazoline class of compounds, with the structure quinazoline-4(1H)-one, substituted with a hydroxyl group at position 8 and a methyl group at position 2. Studies have shown that NU 1025 has inhibitory activity against poly(ADP-ribosyl) polymerase. It is an EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor. NU 1025 belongs to both the quinazoline and phenolic classes. 8-Hydroxy-2-methylquinazoline-4(3H)-one has been reported in Streptomyces, and relevant data are available. Mechanism of action: NU 1025 inhibits PARP1 by binding to its catalytic domain, thereby blocking PARylation modification of proteins involved in DNA base excision repair (BER). In cancer cells, NU 1025 enhances the cytotoxicity of DNA-damaging chemotherapeutic drugs (such as cisplatin and temozolomide) by preventing drug-induced DNA damage repair. In ischemic neurons, NU1025 reduces excessive NAD+ and ATP consumption (caused by PARP overactivation), thereby preventing neuronal necrosis and DNA fragmentation [1,2,3]
- Preclinical therapeutic potential: NU1025 is a well-defined preclinical tool compound with two main applications: (1) chemosensitization in cancer treatment (enhancing the efficacy of platinum-based drugs, alkylating agents, and topoisomerase inhibitors); (2) neuroprotective effects in ischemic stroke (reducing infarct volume and improving neurological function) [1,2,3] - Limitations to clinical translation: NU1025 has lower potency (higher IC50 value) and poorer PARP subtype selectivity compared to clinically approved PARP inhibitors (e.g., olaparib, rucaparib). Its poor water solubility and short in vivo half-life (observed in preliminary pharmacokinetic studies in rats) limit its entry into clinical trials [2,3] |
| Molecular Formula |
C9H8N2O2
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| Molecular Weight |
176.17
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| Exact Mass |
176.058
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| CAS # |
90417-38-2
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| Related CAS # |
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| PubChem CID |
135398517
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| Appearance |
White solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
345.4±44.0 °C at 760 mmHg
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| Melting Point |
253-258ºC
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| Flash Point |
162.7±28.4 °C
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| Vapour Pressure |
0.0±0.8 mmHg at 25°C
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| Index of Refraction |
1.678
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| LogP |
0.35
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
13
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| Complexity |
262
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C2C(=C(C=CC=2)O)NC(C)=N1
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| InChi Key |
YJDAOHJWLUNFLX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C9H8N2O2/c1-5-10-8-6(9(13)11-5)3-2-4-7(8)12/h2-4,12H,1H3,(H,10,11,13)
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| Chemical Name |
8-hydroxy-2-methyl-3H-quinazolin-4-one
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| Synonyms |
NU 1025; NU1025; NU-1025
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (11.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (11.81 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 40% PEG 400+saline: 18mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.6763 mL | 28.3817 mL | 56.7634 mL | |
| 5 mM | 1.1353 mL | 5.6763 mL | 11.3527 mL | |
| 10 mM | 0.5676 mL | 2.8382 mL | 5.6763 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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