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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.
Physicochemical Properties
| Molecular Formula | C24H27F3N8O3 | |
| Molecular Weight | 532.52 | |
| Exact Mass | 532.215 | |
| Elemental Analysis | C, 54.13; H, 5.11; F, 10.70; N, 21.04; O, 9.01 | |
| CAS # | 1034616-18-6 | |
| Related CAS # | 1263293-37-3 (fumarate); 1034616-18-6; | |
| PubChem CID | 49792852 | |
| Appearance | Off-white to light yellow solid powder | |
| Density | 1.6±0.1 g/cm3 | |
| Boiling Point | 757.8±70.0 °C at 760 mmHg | |
| Flash Point | 412.1±35.7 °C | |
| Vapour Pressure | 0.0±2.7 mmHg at 25°C | |
| Index of Refraction | 1.692 | |
| LogP | 0.79 | |
| Hydrogen Bond Donor Count | 3 | |
| Hydrogen Bond Acceptor Count | 12 | |
| Rotatable Bond Count | 7 | |
| Heavy Atom Count | 38 | |
| Complexity | 817 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | FC(OC1C([H])=C([H])C(=C([H])C=1N([H])C1=NC([H])=C2C(C3=C(C(C(N([H])[H])=O)=NN3C([H])([H])C([H])([H])O[H])C([H])([H])C2([H])[H])=N1)N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])(F)F |
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| 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 |
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| 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 |
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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) |
Biological Activity
| 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. |
| Additional Infomation |
Onvansertib is under investigation in clinical trial NCT03303339 (Onvansertib in Combination With Either Low-dose Cytarabine or Decitabine in Adult Patients With Acute Myeloid Leukemia (AML).). Onvansertib is an orally bioavailable, adenosine triphosphate (ATP) competitive inhibitor of polo-like kinase 1 (PLK1; PLK-1; STPK13), with potential antineoplastic activity. Upon administration, onvansertib selectively binds to and inhibits PLK1, which disrupts mitosis and induces selective G2/M cell-cycle arrest followed by apoptosis in PLK1-overexpressing tumor cells. PLK1, named after the polo gene of Drosophila melanogaster, is a serine/threonine kinase that is crucial for the regulation of mitosis, and plays a key role in tumor cell proliferation. PLK1 expression is upregulated in a variety of tumor cell types and high expression is associated with increased aggressiveness and poor prognosis. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (3.76 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2 mg/mL (3.76 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2 mg/mL (3.76 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |