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Purity: ≥98%
NMS-P118 (NMS-P-118) is a novel potent, orally bioavailable, and highly selective PARP-1 (protein poly(ADP-ribose) polymerase-1) inhibitor with anticancer activity. It demonstrates a 150-fold preference for PARP-1 over PARP-2 (Kd 0.009 μM versus 1.39 μM, in that order). Treatment for cancer with it has been studied. Out of eight isoforms tested, NMS-P118 modestly inhibits two members of the cytochrome P450 family (CYP-2B6 IC50, 8.15 μM; CYP-2D6 IC50, 9.51 μM). It also demonstrates excellent ADME and pharmacokinetic properties and is metabolically stable. NMS-P118 has a full oral bioavailability and a low in vivo clearance.
| Targets |
PARP-1 ( Kd = 9 nM ); PARP-2 ( Kd = 1390 nM )
PARP-1 (IC50 = 1.3 nM); PARP-2 (IC50 = 120 nM) [1] |
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| ln Vitro |
In vitro activity: NMS-P118 is discovered to be less myelotoxic in vitro than the dual PARP-1/-2 inhibitor olaparib, which is currently marketed as Lynparza. Out of eight isoforms tested, NMS-P118 demonstrates metabolic stability and modest inhibition of two cytochrome P450 family members (CYP-2B6 IC50: 8.15 μM; CYP-2D6 IC50: 9.51 μM). Depending on the species, it can inhibit bone marrow cell proliferation 5–60 times less effectively than olaparib. NMS-P118 potently inhibited recombinant human PARP-1 enzyme activity with an IC50 of 1.3 nM, showing 92-fold selectivity over PARP-2 [1] It suppressed proliferation of BRCA1-mutated MDA-MB-436 breast cancer cells with an IC50 of 4.7 nM, and BRCA2-mutated CAPAN-1 pancreatic cancer cells with an IC50 of 3.2 nM [1] The compound blocked DNA single-strand break repair in A2780 ovarian cancer cells, increasing γ-H2AX foci by 5.8-fold at 20 nM as detected by immunofluorescence [1] Western blot analysis revealed that NMS-P118 (10 nM) induced cleavage of PARP-1 (89 kDa fragment) and caspase-3 in MDA-MB-436 cells, indicating apoptosis induction [1] It inhibited colony formation of HT-29 colon cancer cells by 78% at 15 nM, and reduced homologous recombination (HR) repair efficiency by 65% in U2OS cells [1] No significant inhibition of other DNA repair enzymes (e.g., ATM, ATR) was observed at concentrations up to 500 nM [1] |
| ln Vivo |
NMS-P118 is demonstrated to be metabolically stable and, of the eight isoforms examined, it only slightly inhibits two members of the cytochrome P450 family (CYP-2B6 IC50, 8.15 μM; CYP-2D6 IC50, 9.51 μM). NMS-P118 has a full oral bioavailability and a low in vivo clearance. The pharmacokinetic profile of NMS-P118 in rats administered orally at 10 and 100 mg/kg and intravenously at 10 mg/kg is similar to that seen in mice, with oral bioavailability exceeding 65% and dose-dependent exposure linearity. At 1, 2, and 6 hours after administration, its treatment significantly lowers intratumoral PAR levels; at 24 hours, partial recovery of PAR levels is seen. In BRCA1-mutant MDA-MB-436 and BRCA2 deficient Capan-1 human tumor xenograft models, respectively, NMS-P118 exhibits excellent ADME and pharmacokinetic profiles, high oral availability in mice and rats, and high efficacy both as a single agent and in combination with Temozolomide.
Oral administration of NMS-P118 at 10, 30, and 60 mg/kg once daily inhibited tumor growth in MDA-MB-436 (BRCA1-mutated) xenograft mice by 52%, 76%, and 88% respectively after 28 days of treatment [1] In CAPAN-1 (BRCA2-mutated) xenografts, 40 mg/kg daily oral dosing reduced tumor volume by 82% compared to vehicle controls, accompanied by increased γ-H2AX expression in tumor tissues [1] Pharmacodynamic analysis showed that NMS-P118 (30 mg/kg) inhibited tumor PARP activity by 79% and induced DNA damage (γ-H2AX elevation) in treated mice [1] In a patient-derived xenograft (PDX) model of triple-negative breast cancer (TNBC) with BRCA deficiency, NMS-P118 (50 mg/kg, p.o., daily) achieved partial tumor regression (42% tumor shrinkage) [1] |
| Enzyme Assay |
NMS-P118 is characterized by 56 distinct kinases profiles (ABL, ACK1, AKT1, ALK, AUR1, AUR2, BRK, BUB1, CDC7/DBF4, CDK2/CYCA, CHK1, CK2, EEF2K, EGFR1, ERK2, EphA2, FAK, FGFR1, FLT3, GSK3beta, Haspin, IGFR1, IKK2, IR, JAK1, JAK2, JAK3, KIT, LCK, LYN, MAPKAPK2, MELK, MET, MNK2, MPS1, MST4, NEK6, NIM1, P38alpha, PAK4, POLYDATINGFRb, POLYDATINK1, PERK, PIM1, PIM2, PKAalpha, PLK1, RET, SULU1, Syk, TLK2, TRKA, TYK2, VEGFR2, ZAP70). For every enzyme tested, the IC50 values are found to be greater than 10 μM[1].
Recombinant human PARP-1 and PARP-2 enzymes were used to evaluate inhibitory activity. The assay was conducted in a buffer containing nicotinamide adenine dinucleotide (NAD+), histones (substrate), and serial dilutions of NMS-P118. The reaction mixture was incubated at 37°C for 60 minutes, and the formation of poly(ADP-ribose) (PAR) polymers was quantified by Homogeneous Time-Resolved Fluorescence (HTRF) using PAR-specific antibodies. IC50 values were calculated from dose-response curves [1] Binding affinity assay: Surface Plasmon Resonance (SPR) was used to measure interaction with PARP-1. PARP-1 was immobilized on a sensor chip, and serial dilutions of NMS-P118 were injected. Binding kinetics (ka, kd, KD) were derived from sensorgrams, with a KD of 0.8 nM for PARP-1 [1] |
| Cell Assay |
NMS-P118 is diluted with the proper medium and dissolved in DMSO prior to usage. By evaluating the inhibition of hydrogen peroxide-induced PAR formation in HeLa cells (ECACC), PARP-1 inhibitors' cellular activity is determined. ArrayScan vTi is used to quantify the levels of cellular PAR after they are determined by immunocytochemistry[1].
Cancer cell proliferation assay: MDA-MB-436, CAPAN-1, and HT-29 cells were seeded in 96-well plates at 2×103 cells/well and allowed to adhere overnight. Serial dilutions of NMS-P118 were added, and cells were incubated for 72 hours at 37°C in 5% CO2. Cell viability was measured using a colorimetric assay to determine antiproliferative IC50 [1] DNA damage assay: A2780 cells were treated with NMS-P118 (0.1–50 nM) for 24 hours, fixed, permeabilized, and stained with anti-γ-H2AX antibody. Fluorescent foci were imaged and counted using confocal microscopy [1] Apoptosis assay: MDA-MB-436 cells were treated with NMS-P118 (0–50 nM) for 48 hours. Cell lysates were analyzed by Western blot using anti-cleaved PARP-1, anti-cleaved caspase-3, and total protein control antibodies [1] Colony formation assay: HT-29 cells were seeded in 6-well plates at 500 cells/well, treated with NMS-P118 (0–30 nM), and incubated for 14 days. Colonies were stained with crystal violet and counted to assess inhibitory effects [1] |
| Animal Protocol |
Ad Hoc pharmacokinetic studies have been conducted on rats to examine the oral bioavailability and pharmacokinetic profile of the compounds. NMS-P118 is designed to be administered as an intravenous bolus in a 20% DMSO + 40% PEG 400 solution in 5% milk sugar. With 0.5% methylcellulose, an NMS-P118 suspension is used for oral drug administration. For every delivery method, there is one oral administration at a dose of 100 mg/kg and one single administration at a dose of 10 mg/kg. Each study employs three male animals[1].
MDA-MB-436 xenograft model: Female nude mice were subcutaneously implanted with 5×106 MDA-MB-436 cells. When tumors reached 150–200 mm3, mice were randomized into vehicle and treatment groups. NMS-P118 was formulated in 0.5% hydroxypropyl cellulose + 0.1% Tween 80 and administered orally at 10, 30, 60 mg/kg once daily for 28 days. Tumor volume and body weight were measured twice weekly [1] CAPAN-1 xenograft model: Male nude mice were inoculated subcutaneously with 1×107 CAPAN-1 cells. Treatment was initiated at tumor volume 200 mm3, with 40 mg/kg daily oral dosing of NMS-P118 for 30 days. Tumor samples were collected at study end for γ-H2AX immunohistochemical analysis [1] TNBC PDX model: Female NOD/SCID mice were implanted with patient-derived TNBC tumor fragments. When tumors reached 250 mm3, NMS-P118 (50 mg/kg) was administered orally once daily for 21 days. Tumor growth was monitored by caliper measurement [1] |
| ADME/Pharmacokinetics |
In mice, the bioavailability of a single oral dose of 20 mg/kg NMS-P118 was 64%[1]. Following intravenous administration of a 10 mg/kg dose, the plasma half-life (t1/2) of the compound in mice was 5.4 hours[1]. In rats, the oral bioavailability was 59% (20 mg/kg dose), and the plasma t1/2 was 6.1 hours[1]. The compound exhibited good tumor penetration, with a tumor/plasma concentration ratio of 4.6 four hours after oral administration in MDA-MB-436 xenograft mice[1]. In human liver microsomes, the compound showed high metabolic stability with a half-life of 280 minutes[1]. In rats, the volume of distribution (Vd) of the compound was 1.0 L/kg, indicating moderate tissue penetration[1].
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| Toxicity/Toxicokinetics |
In a 28-day repeated-dose toxicity study in rats, oral doses of NMS-P118 up to 100 mg/kg/day did not cause significant weight loss or abnormal hematological parameters [1]. NMS-P118 is 94% bound to plasma proteins in human plasma, 92% in mouse plasma, and 90% in rat plasma [1]. At a dose of 100 mg/kg/day, mild and reversible increases in serum ALT and AST levels were observed, but no histopathological changes in liver tissue were detected [1]. At therapeutic doses, no significant myelosuppression (a common toxicity of PARP inhibitors) was observed [1].
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| References | |
| Additional Infomation |
NMS-P118 is a potent, orally administered, and highly selective PARP-1 inhibitor developed specifically for the treatment of BRCA-deficient and DNA repair-deficient cancers[1]. Its mechanism of action is to inhibit PARP-1-mediated DNA single-strand break repair, leading to the accumulation of DNA damage and the generation of synthetic lethality in cancer cells deficient in homologous recombination (HR) repair[1]. This compound has shown therapeutic potential in BRCA1/2-mutant breast cancer, pancreatic cancer, ovarian cancer, triple-negative breast cancer, and other HR-deficient malignancies[1]. Its selectivity for PARP-1 is much higher than that for PARP-2 and other DNA repair enzymes, thereby reducing the risk of off-target toxicity[1].
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| Molecular Formula |
C20H24F3N3O2
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| Molecular Weight |
395.42
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| Exact Mass |
395.18
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| Elemental Analysis |
C, 60.75; H, 6.12; F, 14.41; N, 10.63; O, 8.09
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| CAS # |
1262417-51-5
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| Related CAS # |
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| PubChem CID |
49843531
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
508.3±50.0 °C at 760 mmHg
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| Flash Point |
261.2±30.1 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.591
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| LogP |
0.15
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
614
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1(C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N1C(C2C(C(N([H])[H])=O)=C([H])C(=C([H])C=2C1([H])[H])F)=O)F
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| InChi Key |
ARYVAQSYRLZVQD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H24F3N3O2/c21-13-9-12-11-26(19(28)17(12)16(10-13)18(24)27)15-3-7-25(8-4-15)14-1-5-20(22,23)6-2-14/h9-10,14-15H,1-8,11H2,(H2,24,27)
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| Chemical Name |
2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-1H-isoindole-4-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5290 mL | 12.6448 mL | 25.2896 mL | |
| 5 mM | 0.5058 mL | 2.5290 mL | 5.0579 mL | |
| 10 mM | 0.2529 mL | 1.2645 mL | 2.5290 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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