NMS-P715

MPS1 kinase inhibitor CAS# 1202055-34-2

NMS-P715

Catalog No. BCC6373----Order now to get a substantial discount!

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Chemical structure

NMS-P715

3D structure

Chemical Properties of NMS-P715

Cas No. 1202055-34-2 SDF Download SDF
PubChem ID 44556162 Appearance Powder
Formula C35H39F3N8O3 M.Wt 676.73
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble in DMSO
Chemical Name N-(2,6-diethylphenyl)-1-methyl-8-[4-[(1-methylpiperidin-4-yl)carbamoyl]-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide
SMILES CCC1=C(C(=CC=C1)CC)NC(=O)C2=NN(C3=C2CCC4=CN=C(N=C43)NC5=C(C=C(C=C5)C(=O)NC6CCN(CC6)C)OC(F)(F)F)C
Standard InChIKey JFOAJUGFHDCBJJ-UHFFFAOYSA-N
Standard InChI InChI=1S/C35H39F3N8O3/c1-5-20-8-7-9-21(6-2)28(20)42-33(48)30-25-12-10-23-19-39-34(43-29(23)31(25)46(4)44-30)41-26-13-11-22(18-27(26)49-35(36,37)38)32(47)40-24-14-16-45(3)17-15-24/h7-9,11,13,18-19,24H,5-6,10,12,14-17H2,1-4H3,(H,40,47)(H,42,48)(H,39,41,43)
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.
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.
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.

Biological Activity of NMS-P715

DescriptionNMS-P715 analog is an inhibitor of MPS1, with an IC50 of 84 nM.In Vitro:NMS-P715 analog (Compound 14) is an inhibitor of MPS1, with an IC50 of 84 nM; also less active on Aur-A, CDK2/A and PLK1 (IC50, 1.45, >10, 0.237 μM). In addition, NMS-P715 analog shows inhibitory effect on human tumor cell line (A2780) with an IC50 of 150 nM.

References:
[1]. Caldarelli M, et al. Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors. Bioorg Med Chem Lett. 2011 Aug 1;21(15):4507-11.

Protocol

Kinase Assay [1]
The potency of the compounds (NMS-P715 analog, etc.) towards MPS1, Aur-A, CDK2/A, and PLK1 is determined using either a strong anion exchanger based assay or P81 Multiscreen plate, both based on the specific measurement of radioactive phospho-transfer to the substrate. For each enzyme, the absolute Km values for ATP and the specific substrate are initially determined and each assay is then run at optimized [ATP] (2•αKm) and [substrate] (5•Km) concentrations. These conditions enabled direct comparison of IC50 values across the different kinases to evaluate the selectivity profile. Activity is measured using 5 nM of MPS1 recombinant protein in 50 mM HEPES pH 7.5, 2.5 mM MgCl2, 1 mM MnCl2, 1 mM DTT, 3 μM NaVO3, 2 mM β-glycerophosphate, 0.2 mg/mL BSA, 200 μM P38-βtide substrate-peptide (KRQADEEMTGYVATRWYRAE) and 8 μM ATP with 1.5 nM 33P-γ-ATP[1].

Cell Assay [1]
A2780 ovarian carcinoma cells (ECACC) cultured in RPMI medium, supplemented with 10% fetal calf serum (FCS) and 2 mM L-Glutamine are seeded in 384 well-plates and treated with compounds (NMS-P715 analog, etc.) dissolved in 0.1% DMSO 24 hours after seeding. The cells are incubated at 37°C and 5% CO2 and after 72 hours the plates are processed using CellTiter-Glo assay. Inhibitory activity is evaluated comparing treated versus control data using Assay Explorer software. IC50 of proliferation is calculated using sigmoidal interpolation curve fitting[1].

References:
[1]. Caldarelli M, et al. Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors. Bioorg Med Chem Lett. 2011 Aug 1;21(15):4507-11.

NMS-P715 Dilution Calculator

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NMS-P715 Molarity Calculator

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Preparing Stock Solutions of NMS-P715

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.4777 mL 7.3885 mL 14.7769 mL 29.5539 mL 36.9424 mL
5 mM 0.2955 mL 1.4777 mL 2.9554 mL 5.9108 mL 7.3885 mL
10 mM 0.1478 mL 0.7388 mL 1.4777 mL 2.9554 mL 3.6942 mL
50 mM 0.0296 mL 0.1478 mL 0.2955 mL 0.5911 mL 0.7388 mL
100 mM 0.0148 mL 0.0739 mL 0.1478 mL 0.2955 mL 0.3694 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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Background on NMS-P715

NMS-P715 is a potent and selective inhibitor of MPS1 kinase with IC50 value of 8 nM [1].

Human monopolar spindle 1 (MPS1) kinase is a serine/threonine kinase that plays an important role in spindle assembly checkpoint (SAC) signaling by influencing the stability of the kinetochore-microtubule interaction and controlling chromosome alignment [1].

NMS-P715 is an orally available, selective and ATP-competitive MPS1 kinase inhibitor. In nocodazole-arrested U2OS cells, NMS-P715 promoted massive SAC override with EC50 value of

65 nM. In U2OS cells overexpressing YFP-α-tubulin, NMS-P715 induced mitotic acceleration and reduced mitotic cells. In nocodazole-arrested HeLa cells with MG132, NMS-P715 leads to complete delocalization of MAD1, MAD2, BUB1, BUB3 and Borealin and also reduced MPS1. In A2780 ovarian cancer cells, NMS-P715 reduced G1 phase, caused a flattening in G2/M phase of the cell cycle and subsequently induced apoptosis [1]. In human and murine pancreatic ductal adenocarcinoma (PDAC) cells, NMS-P715 inhibited cell growth [2]. In glioblastoma (GBM) cells, NMS-P715 increased the radiosensitivity of GBM cells by induction of post-radiation mitotic catastrophe and reduced repair of DNA double strand breaks (DSBs) [3].

In nude mice bearing human A2780 ovary carcinoma xenograft model, NMS-P715 (90 mg/kg for 7 days) inhibited tumor growth by 53%. In the A375 melanoma xenograft model, NMS-P715 (100 mg/kg for 10 days) inhibited tumor growth by 43% [1].

References:
[1].  Colombo R, Caldarelli M, Mennecozzi M, et al. Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase. Cancer Res, 2010, 70(24): 10255-10264.
[2].  Slee RB, Grimes BR, Bansal R, et al. Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715. Mol Cancer Ther, 2014, 13(2): 307-315.
[3].  Maachani UB, Kramp T, Hanson R, et al. Targeting MPS1 Enhances Radiosensitization of Human Glioblastoma by Modulating DNA Repair Proteins. Mol Cancer Res, 2015, 13(5): 852-862.

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References on NMS-P715

Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715.[Pubmed:24282275]

Mol Cancer Ther. 2014 Feb;13(2):307-315.

Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.

Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase.[Pubmed:21159646]

Cancer Res. 2010 Dec 15;70(24):10255-64.

MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells.

Description

NMS-P715 analog is the analog of NMS-P715, which is the first selective, ATP-competitive and orally bioavailable MPS1 small-molecule inhibitor(IC50=8 nM); selectively reduces cancer cell proliferation, leaving normal cells almost unaffected.

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