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A-966492

A-966492

Item no.	S2197-1000
Manufacturer	Selleckchem
CASRN	934162-61-5
Amount	1 g
Category	Oncology Food Safety Allergenes Inhibitors & Compound Libraries Small Molecules By Organ Skin Cancer Breast Cancer
Type	Inhibitors
Specific against	other
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	934162-61-5'
Similar products	A-966492
Available
Administration	Orally administrated
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.
Cell lines	C41 cell
Chemical Name	2-(2-fluoro-4-((S)-pyrrolidin-2-yl)phenyl)-3H-benzo[d]imidazole-4-carboxamide
Concentrations	ca.10 nM
Description	A-966492 is a novel and potent inhibitor of PARP1 and PARP2 with Ki of 1 nM and 1.5 nM, respectively.
Dosages	12.5, 25, and 50 mg/kg/day, for 14 days
Features	A-966492 represents a promising, structurally diverse benzimidazole analogue and is being further characterized preclinically.
IC50	1 nM (EC50), 1 nM (Ki), 1 nM (EC50), 1 nM (Ki), 1 nM (EC50), 1 nM (Ki), 1 nM (EC50), 1 nM (Ki), 1 nM (EC50), 1 nM (Ki), 1 nM (EC50), 1 nM (Ki)
In vitro	A-966492 is one of the most potent PARP inhibitors. A-966492 displays excellent potency against the PARP-1 enzyme with a Kiof 1 nM and an EC50 of 1 nM in a whole cell assay. A-966492 significantly enhances the efficacy of TMZ in a dose-dependent manner. In addition, A-966492 is orally bioavailable across multiple species, crosses the blood brain barrier, and appears to distribute into tumor tissue. A-966492 represents a promising, structurally diverse benzimidazole analogue and is being further characterized preclinically. [1]
In vivo	A-966492 also demonstrates 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. In addition, A-966492 has excellent pharmaceutical properties and has demonstrated in vivo efficacy in preclinical mouse tumor models in combination with TMZ and carboplatin, as well as single agent activity in a BRCA1-deficient MX-1 tumor model. A-966492 is further characterized in Sprague Dawley rats, beagle dogs, and cynomolgus monkeys, with A-966492 demonstrating oral bioavailabilities of 34 72% and half-lives of 1.7 1.9 hours. In vivo, A-966492 demonstrates significant enhancement of the efficacy of TMZ in a murine B16F10 syngeneic melanoma model, with the A-966492 combination groups showing superior efficacy. [1]
Incubation Time	30 minutes
Kinase Assay	PARP Enzyme Assay, 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 uM [3H]-NAD+ (1.6 uCi/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 uL volumes in white 96-well plates. Reactions are initiated by adding 50 uL of 2X NAD+ substrate mixture to 50 uL of 2 enzyme mixture containing PARP and DNA. These reactions are terminated by the addition of 150 uL of 1.5 mM benzamide ( 1, 103-fold over its IC50). A 170 uL 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.
Method	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 ug/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).
Molecular Weight (MW)	324, 35
Picture ChemicalStructure Description	A-966492 Chemical Structure
Solubility (25C)	DMSO 65 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Storage	2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO

Note: The presented information and documents (Manual, Product Datasheet, Safety Datasheet and Certificate of Analysis) correspond to our latest update and should serve for orientational purpose only. We do not guarantee the topicality. We would kindly ask you to make a request for specific requirements, if necessary.

All products are intended for research use only (RUO). Not for human, veterinary or therapeutic use.

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