NMS-P937 (NMS1286937; Onvansertib)

Alias: NMS-P937; NMS1286937; NMS-P-937; NMS-P 937; NMS 1286937; NMS-1286937
Cat No.:V1580 Purity: ≥98%
NMS-P937 (also know as NMS-P937;NMS1286937;NMS-P-937; NMS-P 937; Onvansertib) is an orally bioavailable, potent, selective, small-molecule Polo-like Kinase 1 (PLK1) inhibitor with potential antitumor activity.
NMS-P937 (NMS1286937; Onvansertib) Chemical Structure CAS No.: 1034616-18-6
Product category: PLK
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

NMS-P937 (also know as NMS-P937; NMS1286937; NMS-P-937; NMS-P 937; Onvansertib) is an orally bioavailable, potent, selective, small-molecule Polo-like Kinase 1 (PLK1) inhibitor with potential antitumor activity. It exhibits 5000-fold selectivity over PLK2/PLK3 and an IC50 of 2 nM for inhibiting PLK1. NMS-1286937 selectively inhibits PLK1, causing reversible cell-cycle arrest at the G1 and G2 stages without apoptosis in normal cells, and selective G2/M cell-cycle arrest followed by apoptosis in a variety of tumor cells. Following oral administration, NMS-P937 demonstrated activity in vivo in the HCT116 xenograft model. The drug is currently being evaluated in Phase I clinical trials.

Biological Activity I Assay Protocols (From Reference)
Targets
PLK1 (IC50 = 2 nM); FLT3 (IC50 = 510 nM); MELK (IC50 = 744 nM); CK2 (IC50 = 826 nM)
ln Vitro
NMS-P937 demonstrates broad-spectrum antiproliferative activity against cell lines from lymphomas, leukemias, and solid tumors. In A2780 cells, NMS-P937 potently induces a mitotic cell-cycle arrest that is followed by apoptosis.[2]
ln Vivo
NMS-P937 (90 mg/kg/d i.v. or p.o.) significantly inhibits the growth of tumors in mice xenografted with human HCT116 colon adenocarcinoma cells.[1]
NMS-P937 inhibits xenograft tumor growth in mice with HT29, Colo205 colorectal, or A2780 ovarian xenograft tumors. Furthermore, when used with authorized cytotoxic medications, NMS-P937 promotes improved tumor regression and increases animal survival.[2]
Enzyme Assay
Using a trans-phosphorylation assay, the potency of particular compounds and the inhibitory activity of putative kinase inhibitors are assessed. Under optimal buffer and cofactor conditions, a particular tyrosine kinase or serine-threonine kinase will trans-phosphorylate a specific peptide or protein substrate in the presence of ATP traced with 33P-γ-ATP. An excess of the ion exchange Dowex resin is added at the end of the phosphorylation reaction to capture over 98% of the unlabeled ATP and radioactive ATP; the resin then falls to the bottom of the reaction plate due to gravity. The phosphorylated substrate-containing supernatant is then extracted and put into a counting plate for analysis using b-counting. At 25 °C, an end-point assay lasting 60 minutes was used to assess the inhibitory potency of all the kinases that were tested. The substrate and ATP concentrations were maintained at 2 x αKm and >5 x αKm, respectively.
Cell Assay
In suitable medium supplemented with 10% fetal calf serum, cells are seeded into 96- or 384-well plates at densities ranging from 10,000 to 30,000/cm2 for adherent cells and 100,000/mL for nonadherent cells. Cells were treated in duplicate with NMS-P937 serial dilutions after a 24-hour period, and the CellTiter-Glo Assay (Promega) was used to determine the viable cell count 72 hours later. Using the Assay Explorer MDL sigmoidal fitting algorithm, IC50 values were determined. At least two independent experiments were conducted.
Animal Protocol
Female Hsd athymic nu/nu mice, aged 5 to 6 weeks (average weight: 20–22 g), are used for carcinoma xenograft studies. Subcutaneous inoculation is used to inoculate the colorectal HCT116, HT29, ovarian human carcinoma A2780, and colono205 cell lines. Treatment begins the day after randomization and involves giving vehicle or NMS-P937 to mice with a palpable tumor (100-200 mm3) according to prescribed doses and schedules. Tumor growth inhibition (TGI) is calculated and tumor dimensions are routinely measured using Vernier callipers. Reduction of body weight is used to assess toxicity. Severe combined immunodeficient mice (SCID; average weight: 20–22 g) that are 5–6 weeks old are used for leukemia research. Treatments begin with subcutaneous injections of the AmL cell line HL-60 (5×106 cells) and end when the tumor size reaches 200 to 250 mm3. TGI and tumor dimensions are evaluated. Treatments for disseminated models begin two days after intravenous injection of 5x106 AmL primary cells (AmL-PS). Every day, mice are checked for disease-related symptoms, and the median survival period for each group is calculated.
References

[1]. NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor. Bioorg Med Chem Lett. 2011 May 15;21(10):2969-74.

[2]. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther. 2012 Apr;11(4):1006-16.

[3]. The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia. PLoS One. 2013;8(3):e58424.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C24H27F3N8O3
Molecular Weight
532.52
Exact Mass
532.22
Elemental Analysis
C, 54.13; H, 5.11; F, 10.70; N, 21.04; O, 9.01
CAS #
1034616-18-6
Appearance
Solid powder
SMILES
CN1CCN(CC1)C2=CC(=C(C=C2)OC(F)(F)F)NC3=NC=C4CCC5=C(C4=N3)N(N=C5C(=O)N)CCO
InChi Key
QHLVBNKYJGBCQJ-UHFFFAOYSA-N
InChi Code
InChI=1S/C24H27F3N8O3/c1-33-6-8-34(9-7-33)15-3-5-18(38-24(25,26)27)17(12-15)30-23-29-13-14-2-4-16-20(22(28)37)32-35(10-11-36)21(16)19(14)31-23/h3,5,12-13,36H,2,4,6-11H2,1H3,(H2,28,37)(H,29,30,31)
Chemical Name
1-(2-hydroxyethyl)-8-[5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide
Synonyms
NMS-P937; NMS1286937; NMS-P-937; NMS-P 937; NMS 1286937; NMS-1286937
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~42 mg/mL (~78.9 mM)
Water: <1 mg/mL
Ethanol: ~10 mg/mL (~18.8 mM)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.8779 mL 9.3893 mL 18.7786 mL
5 mM 0.3756 mL 1.8779 mL 3.7557 mL
10 mM 0.1878 mL 0.9389 mL 1.8779 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.

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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.

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Biological Data
  • NMS-P937 (NMS1286937)

    PLK1 expression in AML-NS8 cells and activity of PLK1 inhibitor NMS-937in vitroandin vivo.2013;8(3):e58424.

  • NMS-P937 (NMS1286937)

    Leukaemic infiltration of meninges and soft tissues from mice treated with NMS-P937 and cytarabine following a therapeutic schedule.2013;8(3):e58424.

  • NMS-P937 (NMS1286937)

    Mechanism of action of PLK1 inhibitorin vitroandin vivo.2013;8(3):e58424.

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