Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 is a potent PLK1 inhibitor with a mean IC50 of 1.5 nmol/L against the kinase domain of PLK1 at 3 μmol/L ATP. Treatment of HT-29 colorectal cancer cells with TAK-960 for 48 hours resulted in concentration-dependent accumulation of cells in G2–M phase. Accumulation of aberrant spindles was observed following treatment with TAK-960 at 10 or 30 nmol/L. TAK-960 inhibited the proliferation of human cancer cell lines in a concentration-dependent manner, with mean EC50 values ranging from 8.4 to 46.9 nmol/L. To confirm that TAK-960 inhibited PLK1 activity in vivo, mice bearing established HT-29 colorectal tumors were administered a single oral dose (5, 10, or 30 mg/kg) of TAK-960. Plasma exposure to TAK-960 increased in an approximately dose-proportional manner and was partitioned preferentially into the tumor. To further evaluate relationship between PD (pharmacodynamic) response and antitumor activity, TAK-960 was evaluated in mice bearing established HT-29 colorectal tumor xenografts using various regimens. All TAK-960 treatment schedules inhibited tumor growth in a dose-dependent manner without obvious body weight loss. In the subcutaneously implanted MV4-11 human leukemia model, treatment with TAK-960 at 7.5 mg/kg orally once daily for 9 days showed a significant increase in median survival compared with vehicle (39.5 vs. 25 days, respectively; P = 0.0055, Log-rank (Mantel–Cox) test) [2].
作用机制
TAK-960 binds to the ATP-binding pocket of PLK1[2].
TAK-960 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HCT116 cells
8 nM
12 hours
Induced G2/M phase cell cycle arrest, increased sensitivity to radiation
Sci Rep. 2015 Oct 27;5:15666
H1299 cells
8 nM
12 hours
Induced G2/M phase cell cycle arrest, increased sensitivity to radiation
Sci Rep. 2015 Oct 27;5:15666
HeLa cells
8 nM
12 hours
Induced G2/M phase cell cycle arrest, increased sensitivity to radiation
Sci Rep. 2015 Oct 27;5:15666
LS141 cells
50 nM
48 hours
Stayed at 4N with mild apoptosis
Cell Cycle. 2015;14(19):3101-11
CHP100 cells
50 nM
48 hours
Induced apoptosis with Mcl-1 downregulation
Cell Cycle. 2015;14(19):3101-11
MPNST cells
50 nM
48 hours
Induced polyploidy without apoptosis
Cell Cycle. 2015;14(19):3101-11
COLO678 (KRASG12D/PIK3CAWT)
0.1, 0.5, 1, 2 µM
72 hours
To evaluate the effect of TAK-960 on colony formation, showing dose-dependent reduction in colony formation, but with weaker effects.
BMC Cancer. 2018 Feb 5;18(1):136
DLD1 (KRASG13D/PIK3CAD549N E545K)
0.1, 0.5, 1, 2 µM
72 hours
To evaluate the effect of TAK-960 on colony formation, showing dose-dependent reduction in colony formation, but with weaker effects.
BMC Cancer. 2018 Feb 5;18(1):136
HCT116 (KRASG13D/PIK3CAH1047R)
0.1, 0.5, 1, 2 µM
72 hours
To evaluate the effect of TAK-960 on colony formation, showing dose-dependent reduction in colony formation.
BMC Cancer. 2018 Feb 5;18(1):136
WIDR (KRASWT/BRAFV600E/PIK3CAP449T)
0.1, 0.5, 1, 2 µM
72 hours
To evaluate the effect of TAK-960 on colony formation, showing dose-dependent reduction in colony formation.
BMC Cancer. 2018 Feb 5;18(1):136
TAK-960 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Female athymic nude mice
18 colorectal cancer patient-derived xenograft models
Oral gavage
10 mg/kg
Once daily for at least 28 days
To assess the antitumor activity of TAK-960 in vivo, showing 6 out of 18 PDX models were sensitive to TAK-960 (TGII<20).
BMC Cancer. 2018 Feb 5;18(1):136
Nude mice
HeLa tumor xenograft model
Oral
10 mg/kg
Single dose, radiation performed 24 hours later
Increased tumor cell sensitivity to radiation, significantly delayed tumor growth
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