NMS-1286937PLK1 inhibitor, orally bioavailable CAS# 1034616-18-6 |
- INCB024360 analogue
Catalog No.:BCC1647
CAS No.:914471-09-3
Quality Control & MSDS
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Chemical structure
3D structure
| Cas No. | 1034616-18-6 | SDF | Download SDF |
| PubChem ID | 49792852 | Appearance | Powder |
| Formula | C24H27F3N8O3 | M.Wt | 532.52 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | NMS-P937 | ||
| Solubility | DMSO : 21 mg/mL (39.44 mM; Need ultrasonic and warming) | ||
| Chemical Name | 1-(2-hydroxyethyl)-8-[5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide | ||
| SMILES | CN1CCN(CC1)C2=CC(=C(C=C2)OC(F)(F)F)NC3=NC=C4CCC5=C(C4=N3)N(N=C5C(=O)N)CCO | ||
| Standard InChIKey | QHLVBNKYJGBCQJ-UHFFFAOYSA-N | ||
| Standard InChI | 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) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | NMS-1286937 is a potent, selective and orally available PLK1 inhibitor, with IC50 of 2 nM.In Vitro:NMS-1286937 is a potent, selective and orally available PLK1 inhibitor, with IC50 of 2 nM. NMS-1286937 also shows inhibitory activities against FLT3, MELK, and CK2, with IC50s of 510, 744, and 826 nM, respectively[1]. NMS-P937 possesses a pure ATP competitive mechanism with a reversible dissociation and no time dependency. NMS-P937 (10 μM) is selective with a marginal activity of 48% and 40% inhibition on PLK2 and PLK3, respectively. NMS-P937 shows antiproliferative activity against a panel of 137 cell lines, with IC50 values of below 100 nM for 60 of 137 cell lines and higher than 1 μM for only 9 of 137 cell lines[2]. NMS-P937 shows cytotoxic activity against AmL-NS8 cells with IC50 of 36 nM[3].In Vivo:NMS-1286937 (45 mg/kg, i.v.) shows a good tumor growth inhibition with acceptable and reversible body weight loss in CD1 nu/nu mice xenografted with human HCT116 colon adenocarcinoma cells. NMS-1286937 (60 mg/kg, p.o.) also inhibits the growth of tumor on HCT116 xenograft model[1]. NMS-P937 (45 mg/kg, i.v.or 60 mg/kg, p.o) inhibits tumor growth to a comparable degree (TGI, 83% and 79% intravenously and orally, respectively) in HCT116-bearing mice. The combination of NMS-P937 (120 mg/kg given for 4 cycles of 2 consecutive days with 10-day rest) and cytarabine (75 mg/kg for 4 cycles of 5 consecutive days with 7-day rest) in the disseminated leukemia model AmL-PS is well tolerated and clearly showed increased mice survival[2]. NMS-P937 (60 mg/kg bid os per day over 2 days with a 5 day rest) shows good efficacy compared to standard therapies, with a significant increase in median survival time (MST) in the established disease setting[3]. References: | |||||
NMS-1286937 Dilution Calculator
NMS-1286937 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.8779 mL | 9.3893 mL | 18.7786 mL | 37.5573 mL | 46.9466 mL |
| 5 mM | 0.3756 mL | 1.8779 mL | 3.7557 mL | 7.5115 mL | 9.3893 mL |
| 10 mM | 0.1878 mL | 0.9389 mL | 1.8779 mL | 3.7557 mL | 4.6947 mL |
| 50 mM | 0.0376 mL | 0.1878 mL | 0.3756 mL | 0.7511 mL | 0.9389 mL |
| 100 mM | 0.0188 mL | 0.0939 mL | 0.1878 mL | 0.3756 mL | 0.4695 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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NMS-1286937 (NMS-P937) is a potent and selective inhibitor of Polo-like kinase 1 (PLK1) with IC50 value of 2 nM [1].
PLK1 is a serine/threonine protein kinase and plays an important role in the cell cycle control machinery. PLK1 is involved in mitotic entry, bipolar mitotic spindle formation, centrosome duplication, transition from metaphase to anaphase, maintenance of genomic stability and cytokinesis [1].
NMS-1286937 is an orally bioavailable PLK1 inhibitor. In cell lines established from solid tumors, leukemias and lymphomas, NMS-P937 inhibited tumor cell proliferation. In A2780 cells, NMS-P937 caused a G2-M cell-cycle block. In the mitotic phase, NMS-P937 induced apoptotic death with misaligned chromosomes and an aberrant number of spindles poles [2]. In human osteosarcoma (OS) cell lines, NMS-P937 inhibited migration and clonogenic ability of cell lines. In ABCB1-overexpressing, Doxorubicin (DX)-resistant cell lines, combination of NMS-P937 and DX reverted DX-resistance by inhibiting ABCB1 transport activity [3].
In Harlan nu/nu mice, NMS-P937 exhibited a good pharmacokinetic profile with low clearance, high AUC and Cmax, and acceptable oral bioavailability. In mice xenografted with human HCT116 colon adenocarcinoma cells, NMS-P937 (45 mg/kg) inhibited tumor growth by 83% and reduced body weight by 16% [1].
References:
[1]. Beria I, Bossi RT, Brasca MG, et al. 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, 21(10): 2969-2974.
[2]. Valsasina B, Beria I, Alli C, et al. 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, 11(4): 1006-1016.
[3]. Sero V, Tavanti E, Vella S, et al. Targeting polo-like kinase 1 by NMS-P937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance. Invest New Drugs, 2014, 32(6): 1167-1180.
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Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors.[Pubmed:28726132]
Invest New Drugs. 2018 Feb;36(1):85-95.
Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m(2)/day). At the subsequent dose level (48 mg/m(2)/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m(2)/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m(2)/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.
