A-966492

PARP-1/-2 inhibitor, highly potent CAS# 934162-61-5

A-966492

Catalog No. BCC2211----Order now to get a substantial discount!

Product Name & Size Price Stock
A-966492:5mg $105.00 In stock
A-966492:10mg $179.00 In stock
A-966492:25mg $420.00 In stock
A-966492:50mg $735.00 In stock
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Quality Control of A-966492

Quality Control & MSDS

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Chemical structure

A-966492

3D structure

Chemical Properties of A-966492

Cas No. 934162-61-5 SDF Download SDF
PubChem ID 16666333 Appearance Powder
Formula C18H17FN4O M.Wt 324.35
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 100 mg/mL (308.31 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 2-[2-fluoro-4-[(2S)-pyrrolidin-2-yl]phenyl]-1H-benzimidazole-4-carboxamide
SMILES C1CC(NC1)C2=CC(=C(C=C2)C3=NC4=C(C=CC=C4N3)C(=O)N)F
Standard InChIKey AHIVQGOUBLVTCB-AWEZNQCLSA-N
Standard InChI InChI=1S/C18H17FN4O/c19-13-9-10(14-5-2-8-21-14)6-7-11(13)18-22-15-4-1-3-12(17(20)24)16(15)23-18/h1,3-4,6-7,9,14,21H,2,5,8H2,(H2,20,24)(H,22,23)/t14-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of A-966492

DescriptionA-966492 is a novel and potent inhibitor of PARP1 and PARP2 with Ki of 1 nM and 1.5 nM, respectively.
TargetsPARP1PARP2    
IC501 nM1.5 nM    

Protocol

Kinase Assay [1]
The enzyme assay is conducted in buffer containing 50 mM Tris, pH 8.0, 1 mM dithiothreitol(DTT), and 4 mM MgCl2. PARP reactions contains 1.5 μM [3H]-NAD+ (1.6 μCi/mmol), 200 nM biotinylated histone H1, 200 nM slDNA, and 1 nM PARP-1 or 4 nM PARP-2 enzyme. Autoreactions utilizing SPA bead-based detection are carried out in 100 μL volumes in white 96-well plates. Reactions are initiated by adding 50 μL of 2X NAD+ substrate mixture to 50 μL of 2× enzyme mixture containing PARP and DNA. These reactions are terminated by the addition of 150 μL of 1.5 mM benzamide (appr 1×103-fold over its IC50). A 170 μL amount of the stopped reaction mixtures is transferred to streptavidin-coated Flash Plates, incubated for 1 hour, and counted using a TopCount microplate scintillation counter. Ki data are determined from inhibition curves at various substrate concentrations.

Cell Assay [1]
C41 cells are treated with A-966492 for 30 minutes in a 96-well plate. PARP are activated by damaging DNA with 1 mM H2O2 for 10 minutes. Cells are washed with ice-cold phosphate-buffered saline (PBS) once and fixed with prechilled methanol/acetone (7:3) at -20°C for 10 minutes. After they are air-dried, plates are rehydrated with PBS and blocked using 5% nonfat dry milk in PBS-Tween (0.05%) (blocking solution) for 30 minutes at room temperature. Cells are incubated 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, analysis is performed using an fmax Fluorescence Microplate Reader set at the excitation and emission wavelength for FITC or the excitation and emission wavelength for DAPI. PARP activity (FITC signal) is normalized with cell numbers (DAPI).

Animal Administration [1]
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 on study day 0. Tumors are allowed to grow to the indicated size and then randomized to therapy groups (N=10 mice/group). PARP inhibitor therapy begin on day 14, with cisplatin treatment starting on day 16. At various intervals following tumor inoculation, the individual tumor dimensions are serially measured using calibrated microcalipers, and the tumor volumes are calculated.

References:
[1]. Penning TD, et al. Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious

A-966492 Dilution Calculator

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Preparing Stock Solutions of A-966492

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.0831 mL 15.4154 mL 30.8309 mL 61.6618 mL 77.0772 mL
5 mM 0.6166 mL 3.0831 mL 6.1662 mL 12.3324 mL 15.4154 mL
10 mM 0.3083 mL 1.5415 mL 3.0831 mL 6.1662 mL 7.7077 mL
50 mM 0.0617 mL 0.3083 mL 0.6166 mL 1.2332 mL 1.5415 mL
100 mM 0.0308 mL 0.1542 mL 0.3083 mL 0.6166 mL 0.7708 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on A-966492

A-966492 is an inhibitor of PARP-1 with Ki value of 1nM [1].

PARP-1 belongs to the poly(ADP-ribose) polymerases (PARPs) family, it contributes to the resistance happened after cancer therapy. A-966492 is a potent inhibitor of both PARP-1 and PARP-2 (Ki value of 1.5nM) with good potency in C41 whole cells (EC50 value of 1nM). A-966492 shows excellent pharmaceutical properties with oral bioavailabilities of 34-72% and half-lives of 1.7-1.9 h. Additionally, A-966492 can crosses the blood-brain barrier. A-966492 is proved potent in a murine B16F10 syngeneic melanoma model and a BRCA1-deficient MX-1 breast carcinoma model. Meanwhile, it can enhance the efficacy of TMZ and carboplatin in these models [1].

References:
[1] Penning TD, Zhu GD, Gong J, Thomas S, Gandhi VB, Liu X, Shi Y, Klinghofer V, Johnson EF, Park CH, Fry EH, Donawho CK, Frost DJ, Buchanan FG, Bukofzer GT, Rodriguez LE, Bontcheva-Diaz V, Bouska JJ, Osterling DJ, Olson AM, Marsh KC, Luo Y, Giranda VL. Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor. J Med Chem. 2010 Apr 22;53(8):3142-53.

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References on A-966492

Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor.[Pubmed:20337371]

J Med Chem. 2010 Apr 22;53(8):3142-53.

We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b 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.

The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids.[Pubmed:28797568]

Biochem Biophys Res Commun. 2017 Sep 30;491(4):1092-1097.

Radiotherapy is one of the modalities in the treatment of glioblastoma patients, but glioma tumors are resistant to radiation and also chemotherapy drugs. Thus, researchers are investigating drugs which have radiosensitization capabilities in order to improve radiotherapy. PARP enzymes and topoisomerase I enzymes have a critical role in repairing DNA damage in tumor cells. Thus, inhibiting activity of these enzymes helps stop DNA damage repair and increase DSB lethal damages. In the current study, we investigated the combination of TPT as a topoisomerase I inhibitor, and A-966492 as a novel PARP inhibitor for further radiosensitization. U87MG cells (a human glioblastoma cell line) were cultured in Poly-Hema coated flasks to reach 300 mum-diameter spheroids. Treatments were accomplished by using non-toxic concentrations of A-966492 and Topotecan. The surviving fraction of treated cells was determined by clonogenic assay after treatment with drugs and 6 MV X-ray. The gamma-H2AX expression was measured by an immunofluorescence staining method to examine the influence of A-966492, TPT and radiation on the induction of double stranded DNA breaks. Treatments using the A-966492 drug were conducted in concentration of 1 muM. Combining A-966492 and TPT with radiation yielded enhanced cell killing, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) 1.39 and 1.16 respectively. Radio- and chemo-sensitization was further enhanced when A-966492 was combined with both X-ray and TPT, with SER50 of 1.53. Also gamma-H2AX expression was higher in the group treated with a combination of drugs and radiation. A-966492 is an effective PARP inhibitor and has significant radio-sensitivity on U87MG spheroids. By accumulating cells in the S phase and by inhibiting the DNA damage repair, TPT enhanced radio-sensitivity. A-966492 combined with TPT as a topoisomerase I inhibitor had additive radio-sensitizing effects. As a result, applying PARP and topoisomerase I inhibitors can be a suitable strategy for improving radiotherapy in clinics.

Description

A-966492 is a novel and potent inhibitor of PARP1 and PARP2 with Ki of 1 nM and 1.5 nM, respectively.

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