A selective inhibitor of polo-like kinase 1
Polo-like kinases (Plks) are serine/threonine kinases with key roles in cell cycling. TAK-960 is an orally bioavailable, selective inhibitor of Plks with IC50 values of 0.8, 16.9, and 50.2 nM for Plk1, Plk2, and Plk3, respectively.1,2 It exhibits greater than 20-fold selectivity for Plk1 over FAK, MLCK, and the tyrosine protein kinase Fes, and has minimal activity against a panel of 282 other kinases.1,2 It inhibits the proliferation of various cancer cell lines, including MDR1-expressing tumors, and also prevents tumor growth in several human cancer cell xenograft models, including a disseminated model of AML- and MDR1-expressing hematological tumors.1,2
1.Hikichi, Y., Honda, K., Hikami, K., et al.TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimensMol. Cancer Ther.11(3)700-709(2012) 2.Nie, Z., Feher, V., Natala, S., et al.Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1)Bioorg. Med. Chem. Lett.23(12)3662-3666(2013)
Kinase experiment: | The inhibitory activity of TAK-960 is assessed by the TR-FRET (fluorescence resonance energy transfer) assay, which measures the ATP-dependent phosphorylation of a biotinylated substrate peptide corresponding to residues 2,470 through 2,488 of the mTOR protein (Biotin-AGAGTVPESIHSFIGDGLV). A total of 288 kinases are screened for TAK-960 inhibition (1 μM) using HotSpot technology and IC50 values for the selected kinases are determined. |
Cell experiment: | Cells are seeded into 96-well plates at 3,000 to 30,000 cells per well in appropriate medium plus 10% fetal calf serum. 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 using GraphPad Prism software. |
Animal experiment: | The suspension of HeLa cells (2×106 in 100?μL PBS) or H1299 cells (3×106 in 100?μL PBS) is subcutaneously inoculated into the right hind legs of 8-week-old nude mice (BALB/c nu/nu mice). The indicated dose of TAK-960 is orally administered to tumor-bearing mice. In the radiation treatment, tumor xenografts are locally irradiated with the indicated dose of 137Cs γ-rays using a Gammacell 40 Exactor. |
参考文献: [1]. Hikichi Y, et al. TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens. Mol Cancer Ther. 2012 Mar;11(3):700-9. | |
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