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NMS-P118

Cat. No. M5270

NMS-P118 Structure
Size Price Availability Quantity
5mg USD 133 In stock
10mg USD 220 In stock
25mg USD 450 In stock
50mg USD 820 In stock
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Quality Control
  • Current batch:
  • Purity >99%
  • COA
  • MSDS
Biological Activity

In vitro: NMS-P118 is a potent (KD = 0.009 μM) PARP-1 inhibitor, showing 150-fold selectivity over PARP-2 (KD = 1.39 μM). The compound shows high solubility and permeability. In vivo: NMS-P118 is proved to be metabolically stable, it modestly inhibits two cytochrome P450 family members (CYP-2B6 IC50, 8.15 μM; CYP-2D6 IC50, 9.51 μM) out of eight isoforms tested. NMS-P118 has low in vivo clearance, and complete oral bioavailability. The pharmacokinetic profile of NMS-P118 in rat dosed iv at 10 mg/kg and orally at 10 and 100 mg/kg, mirrors that observed in the mouse, with oral bioavailability >65%, and linearity of exposure with dose. Its treatment dramatically decreases intratumoral PAR levels at 1, 2, and 6 h after administration and partial recovery of PAR levels is observed at 24 h. NMS-P118 shows excellent ADME and pharmacokinetic profiles, high oral availability in the mouse and rat, and high efficacy both as a single agent and in combination with Temozolomide in BRCA1-mutated MDA-MB-436 and BRCA2 deficient Capan-1 human tumor xenograft models, respectively.

Protocol
Cell Experiment
Cell lines HeLa cells
Preparation method 6000 cells/well are seeded in 96-well plates in MEM/10% FCS and incubated for 24 h at 37℃, 5% carbon dioxide. Test compounds are then added at the required concentration for 30 min. DNA damage is then induced by adding hydrogen peroxide at the concentration of 0.1 mM for 15 min. Concentration curves are prepared in MEM/10% FCS from compound stocks in DMSO, and final DMSO concentration is 0.002% (v/v). Duplicate wells for each concentration point are prepared with a typical highest compound concentration of 20 μM and serial dilution 1:3. Plates are dried and fixed by adding cold methanol−acetone (70:30) solution for 15 min at room temperature, fixing solution is aspired, and wells are air-dried for 5 min and then dehydrated in PBS. Nonspecific binding sites are blocked by incubating wells for 30 min in PBS containing 5% (w/v) FBS 0.05% Tween 20. Wells are then incubated for 1 h at room temperature in PBS containing anti-PAR mouse monoclonal antibody diluted 1:200 in blocking solution. After three washes in PBS, wells incubate in PBS (w/v) 5% FBS 0.05% Tween 20 containing 2 μg/mL Cy2-conjugated Goat anti-mouse secondary antibody and 1 μg/mL DAPI. After washing further three times in PBS, cellular PAR immunoreactivity is assessed.
Concentrations
Incubation time 30 mins
Animal Experiment
Animal models Balb, Nu/Nu mice
Formulation 10% Tween 80 in 5% dextrose
Dosages 10 mg/kg
Administration i.v.
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
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 resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 395.42
Formula C20H24F3N3O2
CAS Number 1262417-51-5
Purity >99%
Solubility 24 mg/mL in DMSO
Storage at -20°C
References

Free energy calculation provides insight into the action mechanism of selective PARP-1 inhibitor.
Cao R, et al. J Mol Model. 2016 Apr;22(4):74. PMID: 26969680.

Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.
Papeo G, et al. J Med Chem. 2015 Sep 10;58(17):6875-98. PMID: 26222319.

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  Catalog
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Keywords: NMS-P118 supplier, PARP, inhibitors

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