NMS-P937 (NMS1286937) 1034616-18-6

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Molecular Weight:

532.52 NMS-P937 (NMS1286937) is an orally available, selective Polo-like Kinase 1 (PLK1) inhibitor with IC50 of 2 nM, 5000-fold selectivity over PLK2/PLK3. Phase 1.


Biological Activity


NMS-P937 shows a broad-spectrum antiproliferative activity against
different solid tumor, leukemias and lymphomas cell lines. NMS-P937
potently causes a mitotic cell-cycle arrest followed by Apoptosis in
A2780 cells.


In mice xenografted with human HCT116 colon adenocarcinoma cells,
NMS-P937 (90 mg/kg/d i.v. or p.o.) shows a significant tumor growth
inhibition. In mice bearing HT29, Colo205 colorectal, or A2780 ovarian
xenograft tumors, NMS-P937 inhibits xenograft tumor growth. In addition,
NMS-P937, in combination with approved cytotoxic drugs, causes enhanced
tumor regression, and prolongs survival of animals.


Protocol(Only for Reference)


Kinase Assay: [1]

Kinase profile

The inhibitory activity of putative kinase Inhibitors and the potency of selected compounds are determined using a trans-phosphorylation assay. Specific peptide or protein substrates are trans-phosphorylated by their specific serine-threonine or tyrosine kinase, in the presence of ATP traced with 33P-γ-ATP, at optimized buffer and cofactors conditions. At the end of the phosphorylation reaction, more than 98% unlabeled ATP and radioactive ATP is captured by adding an excess of the ion exchange dowex resin; the resin then settles down to the bottom of the reaction plate by gravity. Supernatant, containing the phosphorylated substrate, is subsequently withdrawn and transferred into a counting plate, followed by evaluation by b-counting. Inhibitory potency evaluation for all the tested kinases was performed at 25 °C using a 60 min end-point assay where the concentrations of ATP and substrates are kept equal to 2 x αKm and saturated (>5 x αKm), respectively.

Cell Assay: [2]

Cell lines	137 solid tumor cell lines, and 43 cell lines derived from leukemias and lymphomas
Concentrations	~10 μM
Incubation Time	72 hours
Method	Cells are seeded into 96- or 384-well plates at densities ranging from 10,000 to 30,000/cm2 for adherent and 100,000/mL for nonadherent cells in appropriate medium supplemented with 10% fetal calf serum. After 24 hours, cells were treated in duplicate with serial dilutions of NMS-P937, and 72 hours later, the viable cell number was assessed by the CellTiter-Glo Assay (Promega). IC50 values were calculated with a sigmoidal fitting algorithm (Assay Explorer MDL). Experiments were carried out independently at least twice.

Animal Study: [1]

Animal Models	CD1 nu/nu mice xenografted with human HCT116 colon adenocarcinoma cells
Formulation
Dosages	45 mg/kg bid (i.v.); 90 mg/kg daily (p.o.)
Administration	i.v. or p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	532.52
Formula	C24H27F3N8O3
CAS No.	1034616-18-6

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	N/A

Solubility (25°C) *	In vitro	DMSO	42 mg/mL heating (78.87 mM)
		Water	<1 mg/mL (
		Ethanol	10 mg/mL heating (18.77 mM)
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Name	4,5-dihydro-1-(2-hydroxyethyl)-8-[[5-(4-methyl-1-piperazinyl)-2-(trifluoromethoxy)phenyl]amino]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

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Product Categories : Cell Cycle > PLK Inhibitor