A-966492 is a highly potent and efficacious poly (ADP-ribose) polymerase (PARP) inhibitor with a Ki and EC50 of 1 nM. In addition, it is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.
| Cell Experiment | |
|---|---|
| Cell lines | C41 cell |
| Preparation method | Treating C41 cells with A-966492 for 30 minutes in a 96-well plate . Activating PARP by damaging DNA with 1 mM H2O2 for 10 minutes. Washing cells with ice-cold phosphate-buffered saline (PBS) once and fixing with prechilled methanol/acetone (7:3) at -20 °C for 10 minutes. When they are air-dried, rehydrating plates with PBS and blocked using 5% nonfat dry milk in PBS-Tween(0.05%) (blocking solution) for 30 minutes at room temperature. Incubating cell with anti-PAR antibody 10H (1:50) in blocking solution at room temperature for 60 minutes followed by washing with PBS-Tween20 five times, and incubation with goat antimouse fluorescein 5(6)-isothiocyanate (FITC)-coupled antibody (1:50) and 1 μg/mL 40,6-diamidino-2-phenylindole (DAPI) in blocking solution at room temperature for 60 minutes. After washing with PBS-Tween20 5 times, using an fmax Fluorescence Microplate Reader set at the excitation and emission wavelength for FITC or the excitation and emission wavelength for DAPI to perform analysis. Normalizing PARP activity (FITC signal) with cell numbers (DAPI). |
| Concentrations | ~10 nM |
| Incubation time | 30 minutes |
| Animal Experiment | |
|---|---|
| Animal models | A 0.2 cc amount of a 1:10 dilution of tumor brei in 45% Matrigel and 45% Spinner MEM is injected subcutaneously into the flank of female SCID mice. |
| Formulation | |
| Dosages | 12.5, 25, and 50 mg/kg/day, for 14 days |
| Administration | Orally administrated |
| Molecular Weight | 324.35 |
| Formula | C18H17FN4O |
| CAS Number | 934162-61-5 |
| Solubility (25°C) | DMSO 60 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related PARP Products |
|---|
| DSB-1522
DSB-1522 is a PARP1 inhibitor that can be used in tumor-related studies. |
| DM-5167
DM-5167 is a PARP1 inhibitor that can be used in studies related to triple negative breast cancer. |
| NMS-03305293
NMS-03305293 is a PARP inhibitor with high selectivity for PARP1 isoforms and low DNA capture effect, which specifically kills BRCA mutated tumor cells. In addition, NMS-03305293 can penetrate the blood-brain barrier and can be used in studies related to CNS tumors and brain metastatic tumors. |
| SNV1521
SNV1521 is a potential best-in-class (BIC), highly selective and CNS-permeable PARP1 inhibitor. |
| Basroparib
Basroparib is an orally active selective inhibitor of end-anchor polymerase (TNKS) and an inhibitor of ribose polymerase (PARP) with antitumor activity. |
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