Aurora kinases are a family of 3 highly homologous serine/threonine kinases, and include 3 major members, AURKA, AURKB, and AURKC, that play a well-known role in the regulation of cell cycle and division. CCT137690, a pan-Aurora inhibitor, inhibits the proliferation of cancer cell lines of different origins including colorectal, ovarian, neuroblastoma and leukemia. CCT137690 is a highly selective, orally bioavailable imidazo[4,5-b]pyridine derivative that inhibits Aurora A and B kinases with low nanomolar IC50 values. The IC50 values are 15 nM, 25 nM, and 19 nM for aurora A, B and C, respectively. CCT137690 efficiently inhibits histone H3 and transforming acidic coiled-coil 3 phosphorylation (Aurora B and Aurora A substrates, respectively) in HCT116 and HeLa cells. Continuous exposure of tumor cells to CCT137690 causes multipolar spindle formation, chromosome misalignment, polyploidy, and apoptosis. The PDAC cell lines (PANC1, PANC2.03, CFPAC1, MiaPaCa2, BxPc3, and PANC02) and normal HPDEs cell line were used to identify CCT137690 with anticancer activity against PDAC ( pancreatic ductal adenocarcinoma cancer). Cells were treated with CCT137690 range from 0 - 40 μM for 24 hours, and the PDAC cells viability were significantly decreased by a dose depend manner. In contrast, normal HPDEs were resistant to CCT137690 treatment. Colony formation assays confirmed that the reproductive integrity of the PDAC cells after CCT137690 treatment was significantly reduced. Altogether, these results suggest that CCT137690 has anticancer activity in human PDAC cells. Human PANC1 cells implanted mice were administered CCT137690 orally at 80 mg/kg consecutively for 40 days. Compared with the vehicle control group, administration of CCT137690 effectively reduced tumor growth. Western blot analysis of indicated protein expressions in isolated tumor at day 34 showed that CCT137690 reduced the local phosphorylation of AURKA and GSK3β. These data demonstrated that CCT137690 significantly suppressed PDAC growth in vitro and in vivo through induction of necroptosis[3].
作用机制
CCT137690 binds with Aurora-A enzyme, and the pyridine N and imidazole NH are interacting with Ala213 in the hinge region of the kinase. It occupies the ATP-binding site with the activation loop in a DFG-in conformation. The pyridine N is hydrogen bonded to backbone NH of Ala213 and the imidazole NH to the carbonyl of Ala213[4].
CCT 137690 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HT1080 cells
5 μM
24 h
To detect DCN release induced by CCT137690
Autophagy. 2022 Sep;18(9):2036-2049.
SW48 cells
157 nM
48 h
To evaluate the inhibitory effect of CCT137690 on the proliferation of SW48 cells, results showed that CCT137690 significantly inhibited the proliferation of SW48 cells.
J Exp Clin Cancer Res. 2014 Jan 29;33(1):13.
SW620 cells
430 nM
48 h
To evaluate the inhibitory effect of CCT137690 on the proliferation of SW620 cells, results showed that CCT137690 significantly inhibited the proliferation of SW620 cells.
J Exp Clin Cancer Res. 2014 Jan 29;33(1):13.
HCT116 cells
0.5 or 1 μM
24 h
Induced polyploidy and apoptosis
Mol Cancer Ther. 2011 Nov;10(11):2115-23.
HeLa cells
0.5 μM
24 h
Inhibited Aurora A and B activity
Mol Cancer Ther. 2011 Nov;10(11):2115-23.
Lepto cells
100 nM
24 h
To evaluate the effect of CCT137690 on Lepto cell apoptosis, results showed that CCT137690 significantly induced cell apoptosis.
Cancer Res. 2021 Sep 15;81(18):4723-4735.
HCT116 cells
0.5 μM, 1 μM
24 h
Induced polyploidy and apoptosis
Mol Cancer Ther. 2011 Nov;10(11):2115-23.
HeLa cells
0.5 μM
24 h
Induced multipolar spindle formation and chromosome misalignment
Mol Cancer Ther. 2011 Nov;10(11):2115-23.
KELLY cells
0.33 μM
6 h, 24 h
Inhibited MYCN protein expression and GSK3β phosphorylation
Mol Cancer Ther. 2011 Nov;10(11):2115-23.
Lepto cells
100 nM
72 h
To evaluate the effect of CCT137690 on Lepto cell viability, results showed that CCT137690 significantly inhibited cell viability.
Cancer Res. 2021 Sep 15;81(18):4723-4735.
M1 macrophages
1.25 μM
24 h
AURKA inhibitor CCT137690 restored the sensitivity of M1 cells to TAK1 inhibitor-induced cell death.
Cancer Immunol Immunother. 2020 Nov;69(11):2193-2207.
M2 macrophages
1.25 μM
24 h
AURKA inhibitor CCT137690 had no significant effect on M2 cells' sensitivity to TAK1 inhibitor-induced cell death.
Cancer Immunol Immunother. 2020 Nov;69(11):2193-2207.
MOLM-13 cells
0.023 μM
72 h
To evaluate the inhibitory effect of CCT137690 on the viability of FLT3-ITD+ AML cell line MOLM-13. Results showed that CCT137690 effectively inhibited the growth of MOLM-13 cells.
Leukemia. 2012 Jul;26(7):1462-70.
MV4-11 cells
0.062 μM
72 h
To evaluate the inhibitory effect of CCT137690 on the viability of FLT3-ITD+ AML cell line MV4-11. Results showed that CCT137690 effectively inhibited the growth of MV4-11 cells.
Leukemia. 2012 Jul;26(7):1462-70.
MOLM-13-RES cells
0.08 μM
72 h
To evaluate the inhibitory effect of CCT137690 on the viability of selective FLT3 inhibitor-resistant MOLM-13-RES cells. Results showed that CCT137690 effectively inhibited the growth of MOLM-13-RES cells.
Leukemia. 2012 Jul;26(7):1462-70.
CCT 137690 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
TH-MYCN transgenic mice
Oral gavage
100 mg/kg
Twice daily for 10 days
Significantly inhibited tumor growth
Mol Cancer Ther. 2011 Nov;10(11):2115-23.
NOD/SCID mice
HER2+ LC xenograft models
Intrathecal injection
50 mg/kg
Administered on days 5, 10, and 15
To evaluate the inhibitory effect of CCT137690 combined with anti-GM-CSF neutralizing antibodies on HER2+ LC tumor growth, results showed that the combination treatment significantly inhibited tumor growth and increased survival.
Cancer Res. 2021 Sep 15;81(18):4723-4735.
Mice
TH-MYCN transgenic mice
Oral
100 mg/kg
Twice daily for 10 days
Significantly inhibited tumor growth
Mol Cancer Ther. 2011 Nov;10(11):2115-23.
Athymic mice
MOLM-13 subcutaneous xenograft model
Oral
75 mg/kg
Twice daily for 5 days
To evaluate the inhibitory effect of CCT137690 on the growth of FLT3-ITD+ AML xenografts in vivo. Results showed that CCT137690 significantly inhibited tumor growth, and compared to the selective FLT3 inhibitor MLN518, CCT137690 demonstrated stronger anti-tumor effects.
Leukemia. 2012 Jul;26(7):1462-70.
CCT 137690 动物研究
Dose
Mice: 40 mg/kg, 80 mg/kg[3] (p.o., twice every other day for 2 weeks), 100 mg/kg[1] (p.o., twice daily for 10 days)
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