In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy[3]. AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor with IC50 values of 5 nM, 4 nM and 1 nM for Aurora A, B and C, respectively. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L)[3]. Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types[3].
AMG 900 细胞实验
Cell Line
Concentration
Treated Time
Description
References
DU-145
1 nM and 5 nM
12 hours
To evaluate the effect of AMG 900 on the expression of phosphorylated aurora A/B/C protein in DU-145 cells, the results showed a dose-dependent decrease in phosphorylated aurora expression at concentrations above 1 nmol/L.
Cancer Med. 2014 Oct;3(5):1322-35.
LNCaP
1 nM and 5 nM
12 hours
To evaluate the effect of AMG 900 on the expression of phosphorylated aurora A/B/C protein in LNCaP cells, the results showed a dose-dependent decrease in phosphorylated aurora expression at concentrations above 1 nmol/L.
Cancer Med. 2014 Oct;3(5):1322-35.
PC3
1 nM and 5 nM
12 hours
To evaluate the effect of AMG 900 on the expression of phosphorylated aurora A/B/C protein in PC3 cells, the results showed a dose-dependent decrease in phosphorylated aurora expression at concentrations above 1 nmol/L.
Cancer Med. 2014 Oct;3(5):1322-35.
CU-ACC1
50 nM
2 hours, 24 hours, 48 hours and 72 hours
The combination of AMG 900 with PNU-74654 was more effective in decreasing cell viability compared to either AMG 900 or PNU-74654 alone.
Mol Cell Endocrinol. 2021 May 15;528:111243.
CU-ACC2
50 nM
2 hours, 24 hours, 48 hours and 72 hours
AMG 900 alone showed the best response in decreasing cell viability, and the combination with PNU-74654 did not enhance the effect of AMG 900.
Mol Cell Endocrinol. 2021 May 15;528:111243.
MOLM-13 cells
10 nM
48 hours
AMG 900 inhibited p-histone H3, induced polyploidy, accumulation of p53 protein, apoptosis, and cleavage of Bcl-2 protein in MOLM-13 cells
Mol Cancer Ther. 2018 Dec;17(12):2575-2585.
NCI-H295
50 nM
6 hours and 24 hours
AMG 900 treatment increased CTNNB1 and MYC expression, suggesting that AMG 900 might play a role in activating the Wnt-beta catenin pathway.
Mol Cell Endocrinol. 2021 May 15;528:111243.
AML cell lines
0.1 µM
72 hours
AMG 900 inhibited AML cell growth by inducing polyploidization and/or apoptosis
Mol Cancer Ther. 2018 Dec;17(12):2575-2585.
CHRF-288–11 cells
0.3 µM
72 hours
AMG 900 induced polyploidization and expression of megakaryocyte-lineage markers in CHRF-288–11 cells
Mol Cancer Ther. 2018 Dec;17(12):2575-2585.
Jak2V617F mouse bone marrow cells
0.3 µM
72 hours
AMG 900 significantly increased polyploidization and expression of CD41/CD42 in Jak2V617F mouse bone marrow cells
Mol Cancer Ther. 2018 Dec;17(12):2575-2585.
AMG 900 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
Systemic MOLM-13 xenograft model
Oral
22 mg/kg and 12.6 mg/kg
22 mg/kg for 4 consecutive days, 12.6 mg/kg for 7 consecutive days
AMG 900 significantly reduced tumor burden and inhibited [18F]FLT uptake in skeletal tissues of mice
Mol Cancer Ther. 2018 Dec;17(12):2575-2585.
Mice
DU-145 xenograft model
Gavage
3.75 mg/kg and 7.5 mg/kg
4 days per week for 4 weeks
To evaluate the effect of AMG 900 in combination with vorinostat on tumor growth in the DU-145 xenograft model, the results showed that low-dose AMG 900 in combination with vorinostat significantly inhibited tumor growth, and the effect was similar to that of high-dose AMG 900 alone.
Cancer Med. 2014 Oct;3(5):1322-35.
Mice
COLO 205 tumor xenograft model
Oral
3.75, 7.5, 15 mg/kg
Single dose, assessed after 3 hours
To evaluate the inhibition of p-Histone H3 by AMG 900, results showed significant suppression of p-Histone H3 at 15 mg/kg
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