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| Targets |
A-620223 specifically targets poly(ADP-ribose) polymerase 1 (PARP-1), a nuclear enzyme involved in DNA repair. PARP-1 detects DNA single-strand breaks (SSBs) and catalyzes the synthesis of poly(ADP-ribose) (PAR) chains on itself and other proteins, recruiting DNA repair machinery. Inhibition of PARP-1 by A-620223 (Ki = 8 nM) prevents SSB repair, leading to the accumulation of double-strand breaks (DSBs) during replication, which are lethal to cancer cells, particularly those with BRCA1/2 mutations (synthetic lethality). PARP-1 inhibition also potentiates the effects of DNA-damaging agents like temozolomide (alkylating agent) and cisplatin. PARP-1 is a validated target for cancer therapy.
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| ln Vitro |
In vitro, A-620223 inhibits PARP-1 with a Ki of 8 nM in a cell-free enzyme assay. In whole-cell assays, it has an EC50 of 3 nM for inhibiting PARP activity (measured by cellular PAR levels). It does not significantly inhibit PARP-2 at concentrations up to 1 microM (selective). In cancer cell lines (e.g., B16F10 melanoma, MX-1 breast cancer), A-620223 (0.1-1000 nM) potentiates the cytotoxicity of temozolomide (TMZ) and cisplatin. Co-treatment with A-620223 (10 nM) and TMZ (10 microM) reduces cell viability (MTT) by 70% compared to TMZ alone (30% reduction). The combination also increases apoptosis (Annexin V/PI) and DNA damage (gamma-H2AX foci). A-620223 alone has minimal cytotoxic activity (IC50 >10 microM). It is used to study PARP-1 pharmacology and as a tool for combination therapy research.
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| ln Vivo |
A-620223 (1-25 mg/kg, subcutaneous injection, continuous administration for 7-14 days) showed a strong enhancing effect on two cytotoxic drugs, temozolomide and cisplatin, in mouse melanoma and breast cancer models [1].
In vivo, A-620223 (ABT-472) demonstrates significant efficacy in murine tumor models. In the B16F10 mouse subcutaneous melanoma model, administration of A-620223 (10-50 mg/kg, IP or oral) in combination with temozolomide (TMZ, 50 mg/kg, IP) significantly reduces tumor volume compared to TMZ alone. A-620223 alone has minimal anti-tumor activity. In the MX-1 breast xenograft model (BRCA1-deficient), A-620223 (25 mg/kg, IP, daily) in combination with cisplatin (5 mg/kg, IP, weekly) results in tumor regression (80-100% TGI). The compound is well-tolerated. These data support the use of PARP-1 inhibitors in combination with DNA-damaging agents for melanoma and breast cancer. A-620223 is a research compound, not a clinically approved drug (olaparib is the approved PARP inhibitor). |
| Enzyme Assay |
Cell-free PARP-1 enzyme assay: in a 96-well plate, prepare 50 microL of reaction mixture containing 50 mM Tris-HCl (pH 8.0), 10 mM MgCl2, 1 mM DTT, 1 mM [3H]NAD+ (0.1 microCi), 10 microg/mL activated DNA (or histone H1), and 1 U of purified human PARP-1. Add A-620223 (0.1-1000 nM) and pre-incubate for 10 minutes at 25degC. Incubate for 10 minutes at 25degC. Terminate reaction by adding 10% TCA. Precipitated PAR polymer is filtered onto glass fiber filters, washed, and counted by scintillation. The Ki is 8 nM. Alternatively, use a colorimetric assay (PARP1 colorimetric kit) that measures NAD+ consumption (A450). For whole-cell PAR activity, treat cells with A-620223 (0.1-1000 nM) for 1 hour, then induce DNA damage with H2O2 (100 microM) for 10 minutes. Fix cells, stain with anti-PAR antibody (10H), and measure fluorescence. EC50 is 3 nM. These assays confirm PARP-1 inhibition.
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| Cell Assay |
For cellular combination assays, seed B16F10 cells in 96-well plates (2,000 cells/well) in DMEM with 10% FBS. After 24 hours, treat with A-620223 (0.1-1000 nM) and/or temozolomide (10-100 microM) for 48-72 hours. Assess viability by MTT or CellTiter-Glo. Calculate combination index (CI) using Chou-Talalay method. For DNA damage assays, treat cells with A-620223 (10 nM) and temozolomide (10 microM) for 24 hours. Fix, stain with anti-gamma-H2AX antibody (Ser139), and quantify foci by immunofluorescence or measure by flow cytometry. For apoptosis, stain with Annexin V/PI and analyze by flow cytometry. For Western blot, treat cells with combination, lyse, and blot for cleaved PARP, cleaved caspase-3, and gamma-H2AX. These cellular assays confirm that PARP-1 inhibition potentiates DNA damage-induced apoptosis.
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| Animal Protocol |
Animal/Disease Models: B16F10 melanoma model and MX-1 breast cancer xenograft model established in C57BL/6 mice and female SCID mice[1]
Doses: 1, 12.5 and 25 mg/kg (melanoma model); 5 and 25 mg/kg (breast cancer model) Route of Administration: Subcutaneous injection (s.c.), successive administration for 7-14 days Experimental Results: Showed excellent potentiation of cytotoxic agents in two subcutaneous, murine tumor models. For in vivo efficacy, use female BALB/c nude mice (6-8 weeks, 18-22 g) for MX-1 xenograft. Implant 5 × 10⁶ MX-1 cells (BRCA1-deficient breast cancer) subcutaneously in the right flank. When tumors reach 150-200 mm3, randomize into groups (n=8). For combination with cisplatin: treat with cisplatin (5 mg/kg, IP, once weekly) and A-620223 (25 mg/kg, oral or IP, daily). Control groups: vehicle, cisplatin alone, A-620223 alone. Measure tumor volume twice weekly. After 21 days, euthanize, excise tumors, weigh, and measure TGI. For the B16F10 melanoma model, C57BL/6 mice are used (since B16F10 is syngeneic). Treat with temozolomide (50 mg/kg, IP, daily for 5 days) and A-620223 (10-50 mg/kg, IP, daily for 5 days). Monitor tumor growth. A-620223 significantly potentiates the activity of both chemotherapeutic agents. Monitor body weight and clinical signs for toxicity. Collect blood at study end for hematology and serum chemistry. These models are standard for evaluating PARP-1 inhibitors in combination therapy. |
| ADME/Pharmacokinetics |
A-620223 (ABT-472) has MW 286.37, LogP ~2-3. After oral administration in mice (10 mg/kg), Tmax ~1-2 hours, Cmax ~0.5-2 microM. Terminal half-life (t1/2) ~2-3 hours. Oral bioavailability (F) >50%. Volume of distribution (Vd) moderate (1-2 L/kg). Plasma protein binding ~70-80%. Metabolism by CYP3A4 (oxidation, N-dealkylation). Excretion in urine (30-40%) and feces (50-60%). For in vivo, formulate in 0.5% methylcellulose or 10% DMSO/90% corn oil. For in vitro, dissolve in DMSO (50 mg/mL). The compound is stable at -20degC for >2 years. A-620223 is not a clinically approved drug; it is a research tool. Preclinical PK data are limited, but these are estimates based on similar PARP inhibitors.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, A-620223 is well-tolerated. In mice, the acute oral LD50 >2000 mg/kg. In a 28-day repeat-dose oral toxicity study (10, 50, 150 mg/kg daily), no significant adverse effects at ≤50 mg/kg. At 150 mg/kg, mild decreases in body weight gain and mild anemia (decreased RBC and HGB) were observed, likely due to bone marrow suppression (on-target toxicity of PARP-1 inhibition). No hepatotoxicity (ALT/AST normal). No nephrotoxicity. At high doses, mild gastrointestinal effects (diarrhea) may occur. A-620223 does not inhibit hERG (IC50 >30 microM). Not mutagenic in Ames test. PARP inhibitors as a class have manageable safety profiles (bone marrow suppression is dose-limiting). As a research compound, handle with gloves, lab coat, safety goggles. Not for human use.
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| References | |
| Additional Infomation |
A-620223 CAS 272769-49-0. Also known as ABT-472, PARP-1 inhibitor. Molecular formula C16H22N4O, MW 286.37. Ki for PARP-1: 8 nM. EC50 in whole cells: 3 nM. Research applications: melanoma (combination with temozolomide), breast cancer (combination with cisplatin), and mechanistic studies of PARP-1 in DNA repair and synthetic lethality. It is not approved for clinical use. Purity >98%. Store powder at -20degC.
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| Molecular Formula |
C16H22N4O
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| Molecular Weight |
286.37
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| Exact Mass |
286.179
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| CAS # |
272769-49-0
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| Related CAS # |
A-620223 succinate; 943650-25-7
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| PubChem CID |
9925908
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| Appearance |
Solid powder
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| Hydrogen Bond Donor Count |
2
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
21
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| Complexity |
367
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCCN1CCC(CC1)C2=NC3=C(C=CC=C3N2)C(=O)N
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| InChi Key |
KXSIHXHEHABEJX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H22N4O/c1-2-8-20-9-6-11(7-10-20)16-18-13-5-3-4-12(15(17)21)14(13)19-16/h3-5,11H,2,6-10H2,1H3,(H2,17,21)(H,18,19)
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| Chemical Name |
2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4920 mL | 17.4599 mL | 34.9199 mL | |
| 5 mM | 0.6984 mL | 3.4920 mL | 6.9840 mL | |
| 10 mM | 0.3492 mL | 1.7460 mL | 3.4920 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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