ArtNr |
S1239-10 |
Hersteller |
Selleckchem
|
CAS-Nr. |
1137868-52-0 |
Menge |
10 mg |
Kategorie |
|
Typ |
Inhibitors |
Specific against |
other |
ECLASS 10.1 |
32160490 |
ECLASS 11.0 |
32160490 |
UNSPSC |
12000000 |
Lieferbar |
|
Administration |
Oral dosing |
Animal Models |
Athymic nude mice (BALB/cAJc1-nu/nu), severe combined immunodeficiency (SCID) mice (C.B17-Icr- scid/scid Jcl) or NOD-scid mice (NOD.CB17-Prkdc scid/J) |
Cell lines |
Human tumor cell lines including those with TP53 or KRAS mutations or MDR1 overexpression |
Chemical Name |
4-(9-cyclopentyl-7, 7-difluoro-5-methyl-6-oxo-6, 7, 8, 9-tetrahydro-5H-pyrimido[4, 5-b][1, 4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide |
Clinical Trials |
TAK-960 is currently in Phase I clinical trial in patients with advanced nonhematologic malignancies. |
Concentrations |
0.001-1uM |
Description |
TAK-960 is a novel, potent and selective Plk1 inhibitor with IC50 of 8 nM. |
Dosages |
30 mg/kg |
Features |
The discovery of TAK -960 provides an interesting example of how the addition of fluorine atoms during optimization significantly alters the attributes of the leads series. |
Formulation |
Suspended in 0.5% methyl cellulose |
IC50 |
8 nM [1], 8 nM [1], 8 nM [1], 8 nM [1], 8 nM [1], 8 nM [1] |
In vitro |
TAK-960 has shown activity in several tumor cell lines including those that express multidrug resistant protein 1 (MDR1). [1] Consistent with PLK1 inhibition, TAK-960 treatment gives rise to accumulation of G2/M cells, aberrant "polo" mitosis morphology, and increases phosphorylation of histone H3 (pHH3). [1] TAK-960 inhibits proliferation of multiple cancer cell lines, with mean EC50 values ranging from 8.4 to 46.9 nM, but not in non-dividing normal cells (EC50 >1, 000 nM). The mutation status of TP53 or KRAS and MDR1 expression does not correlate with the potency of TAK-960 in the cell lines tested. [1] |
In vivo |
In animal models, oral administration of TAK-960 increases pHH3 in a dose-dependent manner and significantly inhibits the growth of HT-29 colorectal cancer xenografts. [1] Treatment with once-daily TAK-960 exhibits significant efficacy against multiple tumor xenografts, including an Doxorubicin/Paclitaxel-resistant xenograft model and a disseminated leukemia model. [1] |
Incubation Time |
72 hours |
Kinase Assay |
Biochemical kinase inhibition assays, The inhibitory activity of TAK-960 is assessed by the TR-FRET assay, which measures the ATP-dependent phosphorylation of a biotinylated substrate peptide corresponding to residues 2470 through 2488 of the mammalian target of rapamycin protein (Biotin-AGAGTVPESIHSFIGDGLV). A total of 288 kinases are screened for TAK-960 inhibition (1 uM) using HotSpotSM technology and IC50 values for the selected kinases are determined. |
Method |
Cells are seeded into 96-well plates at 3-30, 103 cells/well in appropriate medium plus 10% fetal calf serum (FCS). After 24 hours, cells are treated with serial dilutions of TAK-960, and 72 hours later, the number of viable cells is assessed using the CellTiter-Glo Assay. Calculation of EC50 values and statistical analysis are done. |
Molecular Weight (MW) |
561, 6 |
Picture ChemicalStructure Description |
TAK-960 Chemical Structure |
Storage |
2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO |
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