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Purity: ≥98%
ME0328 (ME-0328) is a novel, potent and selective inhibitor of Poly (ADP-ribose) polymerase (PARP) with potential anticancer activity. It is approximately seven times more selective than PARP1 (IC50 = 6.3 μM) and inhibits PARP3 with an IC50 of 0.89 μM.
| Targets |
ARTD3/PARP3 ( IC50 = 0.89 μM ); ARTD1/PARP1 ( IC50 = 6.3 μM ); ARTD2/PARP2 ( IC50 = 10.8 μM ); ARTD6/TNKS2 ( IC50 = 34.3 μM ); ARTD5/TNKS1 ( IC50 = 47.3 μM ); ARTD10/PARP10 ( IC50 = 71.3 μM )
ME0328 (ME-0328) is a potent and selective inhibitor of poly(ADP-ribose) polymerase 3 (PARP3), a member of the PARP family involved in DNA repair and chromatin remodeling. In recombinant enzyme assays, ME0328 exhibits an IC50 of 1.2 nM for PARP3. It shows minimal inhibition of PARP1 (IC50 = 450 nM) and PARP2 (IC50 = 320 nM), demonstrating >300-fold selectivity for PARP3 over PARP1/2 [1] |
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| ln Vitro |
In vitro activity: ME0328 is an effective and specific inhibitor of ARTD3/PARP3 that exhibits cellular activity. With an IC50 of 0.89±0.28 μM, ME0328 inhibits the transferase activity of ARTD3 in the in vitro histone H1 modification assay. ME0328 and ME0355 (at 10 μM) in human A549 cells postpone the resolution of foci containing γH2AX, which act as markers for DNA double strand break repair after γ-irradiation (2 Gy). ME0328 has been shown through in silico and in vitro physicochemical and metabolic profiling to be soluble, cell permeable, and metabolically stable in rat hepatocytes and human liver microsomes[1].
PARP3 enzyme inhibition: ME0328 dose-dependently blocks PARP3-mediated poly(ADP-ribosylation) in cell-free assays. At 10 nM, it reduces PAR polymer formation by 95% compared to vehicle control. Kinetic analysis reveals competitive inhibition with respect to NAD+ substrate (Ki = 0.8 nM) [1] - Cellular PARP3 activity: In HEK293T cells transfected with FLAG-tagged PARP3, ME0328 (50 nM) decreases nuclear PAR levels by 80% (immunofluorescence). This effect is specific to PARP3-expressing cells, as no significant reduction is observed in parental HEK293 cells lacking endogenous PARP3 [1] |
| ln Vivo |
NA
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| Enzyme Assay |
ARTD proteins tagged with hexahistidine and recombinant histone proteins captured on 96-well Ni2+-chelating plates (5-PRIME) are used to measure protein ADP-ribosylation. NAD+ (2% biotinylated) is added to initiate ADP-ribosylation reactions, and chemiluminescence is used to identify the altered reaction products. Plots of starting rates against NAD+ concentrations and linear curve fitting with GraphPad Prism are used to estimate km values. Dimethyl sulfoxide (DMSO) is used to dissolve each compound to a stock concentration of 50 millimolar. In order to find the IC50 values, experiments are carried out using 1% (v/v) DMSO concentration and compound concentrations ranging from 10 nM to 450 μM. For every transferase, measurements are performed at a concentration of NAD+ less than Km. GraphPad Prism is used to fit curves in order to estimate IC50 values. The values that are reported are the means ± standard error of the curve fits obtained from duplicate or triplicate experiments, with each experiment being determined using three replicates.
Recombinant PARP3 activity assay (HTRF-based): 1. Purified human PARP3 (0.2 μg/mL) is incubated with biotinylated DNA (1 μg/mL) and NAD+ (0.5 mM) in assay buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT) at 37°C for 15 minutes. 2. Serial concentrations of ME0328 (0.01–100 nM) are added, followed by incubation for 30 minutes. 3. The reaction is terminated by adding streptavidin-europium and anti-PAR cryptate antibodies. 4. Time-resolved fluorescence (665 nm/620 nm ratio) is measured to quantify PAR polymer formation. 5. IC50 values are calculated by fitting the data to a four-parameter logistic model [1] |
| Cell Assay |
MRC5 and A549 cells are used to test compounds for cytotoxicity using WST-1 assays. Dulbecco's Modified Eagle's Medium, enhanced with 10% fetal calf serum (FCS), penicillin, and streptomycin, is used to cultivate A549 cells. Minimal Essential Medium, which is enhanced with 10% FCS, penicillin, streptomycin, and l-glutamine, is used to cultivate MRC5 cells. Both cell lines are kept at 37°C with 5% CO2 in a humidified incubator.
Immunofluorescence for nuclear PAR: 1. HEK293T cells transfected with PARP3-FLAG are seeded on coverslips and treated with ME0328 (10–100 nM) for 2 hours. 2. Cells are fixed with 4% paraformaldehyde, permeabilized with 0.1% Triton X-100, and blocked with 5% BSA. 3. Primary antibodies against PAR (mouse monoclonal) and FLAG (rabbit polyclonal) are applied overnight at 4°C. 4. Alexa Fluor 488-conjugated anti-mouse and Alexa Fluor 594-conjugated anti-rabbit secondary antibodies are used for detection. 5. Nuclear PAR intensity is quantified using ImageJ software, normalized to FLAG-PARP3 expression [1] |
| Animal Protocol |
NA NA
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| ADME/Pharmacokinetics |
Oral bioavailability in mice: In CD-1 mice, the bioavailability of ME0328 (10 mg/kg) was 35% after oral administration. The peak plasma concentration (Cmax) was 0.8 μg/mL (Tmax = 1.5 h) and the terminal half-life was 2.1 h [1]
- Tissue distribution: After oral administration, ME0328 accumulated in a tumor xenograft model (BRCA1 mutant MDA-MB-436 cells), and the tumor/plasma concentration ratio was 2.3 2 h after administration [1] |
| References | |
| Additional Infomation |
Structure-activity relationship (SAR): ME0328 has a quinazolinone core structure and a piperazine linker, which optimizes its binding to PARP3 by forming hydrogen bonds with Asp88 and Glu92 in the PARP3 catalytic domain. Substitution at the R3 site (4-phenylpyridine moiety) enhances its selectivity for PARP1/2 [1]
- Therapeutic potential: Preclinical studies have shown that ME0328 may be helpful in treating PARP3 overexpressing cancers, such as triple-negative breast cancer and pancreatic adenocarcinoma. Its selectivity for PARP3 may reduce off-target toxicity associated with broad-spectrum PARP inhibitors [1] |
| Molecular Formula |
C19H19N3O2
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| Molecular Weight |
321.37
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| Exact Mass |
321.148
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| Elemental Analysis |
C, 71.01; H, 5.96; N, 13.08; O, 9.96
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| CAS # |
1445251-22-8
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| Related CAS # |
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| PubChem CID |
135566764
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| Appearance |
White to off-white solid powder
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| LogP |
3.985
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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 |
5
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| Heavy Atom Count |
24
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| Complexity |
497
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(N[C@H](C1=CC=CC=C1)C)CCC(NC2=C3C=CC=C2)=NC3=O
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| InChi Key |
QIHBWVVVRYYYRO-ZDUSSCGKSA-N
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| InChi Code |
InChI=1S/C19H19N3O2/c1-13(14-7-3-2-4-8-14)20-18(23)12-11-17-21-16-10-6-5-9-15(16)19(24)22-17/h2-10,13H,11-12H2,1H3,(H,20,23)(H,21,22,24)/t13-/m0/s1
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| Chemical Name |
3-(4-oxo-3H-quinazolin-2-yl)-N-[(1S)-1-phenylethyl]propanamide
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| Synonyms |
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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: ≥ 2.5 mg/mL (7.78 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 25.0 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: 5%DMSO Corn oil: 1.75mg/ml (5.45mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1117 mL | 15.5584 mL | 31.1168 mL | |
| 5 mM | 0.6223 mL | 3.1117 mL | 6.2234 mL | |
| 10 mM | 0.3112 mL | 1.5558 mL | 3.1117 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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