NMS-P118

製品コードS8363 バッチS836302

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C20H24F3N3O2
分子量 395.42 CAS No. 1262417-51-5
Solubility (25°C)* 体外 DMSO 79 mg/mL warmed with 50ºC water bath (199.78 mM)
Ethanol 10 mg/mL warmed with 50ºC water bath (25.28 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 NMS-P118 is a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles, showing 150-fold selectivity for PARP-1 over PARP-2 (Kd 0.009 μM vs 1.39 μM, respectively).
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[1].
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[1].

プロトコル(参考用のみ)

細胞アッセイ 細胞株 HeLa cells
濃度 --
反応時間 30 mins
実験の流れ 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.
動物実験 動物モデル Balb, Nu/Nu mice
投薬量 10 mg/kg
投与方法 i.v.

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Haploinsufficiency of ZNF251 causes DNA-PKcs-dependent resistance to PARP inhibitors in BRCA1-mutated cancer cells [ Res Sq, 2023, rs.3.rs-2688694] PubMed: 37066268
Haploinsufficiency of ZNF251 causes DNA-PKcs-dependent resistance to PARP inhibitors in BRCA1-mutated cancer cells [ Res Sq, 2023, rs.3.rs-2688694] PubMed: 37066268
Poly (ADP-ribose) polymerase 1 (PARP1) inhibition promotes pulmonary metastasis of osteosarcoma by boosting ezrin phosphorylation [ Int J Biol Sci, 2022, 18(3):1238-1253] PubMed: 35173550
CRISPR screening identifies novel PARP inhibitor classification based on distinct base excision repair pathway dependencies [ bioRxiv, 2021, 10.1101/2020.10.18.333070] PubMed: None
Response of Breast Cancer Cells to PARP Inhibitors Is Independent of BRCA Status. [ J Clin Med, 2020, 30;9(4)] PubMed: 32235451
Enabling drug discovery for the PARP protein family through the detection of mono-ADP-ribosylation [ Biochem Pharmacol, 2019, 10.1016/j.bcp.2019.05.007] PubMed: 31075269
DNA‑PKcs PARylation regulates DNA‑PK kinase activity in the DNA damage response. [ Mol Med Rep, 2019, 20(4):3609-3616] PubMed: 31485633

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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