The Aurora family of serine/threonine kinases, which consists of Aurora A, B and C, plays an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Tozasertib is a potent inhibitor of all three Aurora kinases, with Ki(app) values of 0.6 nM, 18 nM and 4.6 nM for Aurora A, B and C, respectively, and showed much less potency to FLT3 and Bcr-Abl with Ki(app) values of 30 nM. Tozasertib potently inhibited the proliferation of a wide variety of tumor cell types from different original tissues with IC50 values ranging in 15-113 nM, including HCT116, LS174T (colorectal), HL60 (leukemia), MD-MBA-231, ZR-75-1, MCF-7 (breast), PC3 (prostate), MIA PaCa2 (pancreatic), A375 (melanoma) and HeLa (cervical). In a further study, it was found that leukemia, lymphoma and colorectal cancer cell lines were particularly sensitive to Tozasertib on growth inhibition attributable to apoptosis. Tozasertib can cause accumulation of HeLa cells with ≥4N DNA content and inhibits histone H3 phosphorylation on Ser10, suggesting the inhibition of Aurora B. These can also be observed in in vivo model. Tozasertib at 75 mg/kg, twice a day intraperitoneally, caused mean tumor volumes reduced by 98% in a human AML (HL-60) xenograft model. Administration of Tozasertib by i.v. infusion at 1 mg/kg/h, 3 d per week, caused tumor regression in four of seven nude rats bearing established HCT116 (colon) tumors[1].
作用机制
Tozasertib binds to the ATP-binding site of the Aurora kinases.[1]
Tozasertib/陶扎色替 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Patched mutant tumor cells
0.15 nM - 1.5 µM
48 hours
To evaluate the inhibitory effect of CCT129202 on tumor cell proliferation, results showed significant inhibition of tumor cell proliferation.
Cancer Res. 2013 Oct 15;73(20):6310-22.
GFP-AZI2 -4OHT cells
5 µM
24 h
Screen for compounds that induce AZI2 puncta formation
Autophagy. 2024 Mar;20(3):525-540.
HCT-116 cells
10 μM
24 h or 48 h
To assess the effect of Tozasertib on DNA content in HCT-116 cells, results showed that Tozasertib treatment led to polyploidy.
Nat Biotechnol. 2016 Apr;34(4):419-23.
MDA-MB-468 breast cancer cells
1-10 μM
2 h
To evaluate the inhibitory effect of Tozasertib on Aurora A Thr288 autophosphorylation, results showed effective inhibition of Aurora A activity at concentrations ranging from 1-10 μM.
J Med Chem. 2012 Sep 13;55(17):7392-7416.
SKHep1 liver cancer cells
0.2 µM
7 days
Induced cellular senescence, followed by treatment with Ouabain, Digoxin, or ABT-263, effectively killing senescent cancer cells.
Nat Metab. 2019 Nov;1(11):1074-1088.
A549 lung cancer cells
0.2 µM
7 days
Induced cellular senescence, followed by treatment with Ouabain, Digoxin, or ABT-263, effectively killing senescent cancer cells.
Nat Metab. 2019 Nov;1(11):1074-1088.
HCT-116 cells
10 μM
24 h or 48 h
To evaluate the effect of Tozasertib on DNA content in HCT-116 cells
Nat Biotechnol. 2016 Apr;34(4):419-23.
Jurkat T cells
10 μM
24 h
To assess the effect of Tozasertib on cytokine release from T cells, results showed that Tozasertib significantly upregulated the transcriptional expression of TNF-α, IFN-γ, and GZMB.
Neoplasia. 2024 Feb;48:100966.
H23 cells
10 μM
24 h
Tozasertib inhibited AURKA and increased the expression of GLI-1 and KRAS
Cell Death Dis. 2024 Jan 16;15(1):56.
SKHep1 cells
0.2 μM
7 days
Induced senescence in SKHep1 cells
Nat Metab. 2019 Nov;1(11):1074-1088.
A549 cells
0.2 μM
7 days
Induced senescence in A549 cells
Nat Metab. 2019 Nov;1(11):1074-1088.
B16F10 cells
10 μM
24 h
To analyze the effect of Tozasertib on the transcriptome of B16F10 cells, results showed that Tozasertib significantly affected cell cycle-related pathways and immune response pathways.
Neoplasia. 2024 Feb;48:100966.
H358 cells
10 μM
24 h
Tozasertib inhibited AURKA and increased the expression of GLI-1 and KRAS
Cell Death Dis. 2024 Jan 16;15(1):56.
Tozasertib/陶扎色替 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
B16F10 melanoma xenograft model
Intraperitoneal injection
50 mg/kg
Once daily for 7 days
To evaluate the anti-tumor immune effects of Tozasertib in a melanoma xenograft model, results showed that Tozasertib significantly suppressed tumor growth and reduced the number of Treg cells in the tumors.
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