Background
CCT129202, a derivative of the piperazinyl imidazo[4,5-b] pyridine scaffold, is a novel and potent inhibitor of Aurora kinase that ATP-competitively inhibits Aurora A, Aurora B and Aurora C with values of 50% inhibition concentration IC50 of 0.042, 0.198 and 0.227 μmol/L respectively. CCT129202 exhibits anti-cancer activity against multiple human tumor cell lines through inhibiting proliferation, inducing apoptosis and delaying mitosis, abrogation of nocodazole-induced mitotic arrest and spindle defects. Recent study results have shown that CCT129202 inhibits the growth of HCT116 xenografts in nude mice and induces the production of a cyclin-dependent kinase inhibitor, p21, in HCT116 cells consequently leading to Rb hypophosphorylation.
Reference
[1].Chan F, Sun C, Perumal M, Nguyen QD, Bavetsias V, McDonald E, Martins V, Wilsher NE, Raynaud FI, Valenti M, Eccles S, Te Poele R, Workman P, Aboagye EO, Linardopoulos S. Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity. Mol Cancer Ther. 2007; 6(12 Pt1): 3147-3157.
Protocol
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Cell experiment [1]:
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Cell lines
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MV4-11 cell lines, MDA-MB-157 cell lines
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Preparation method
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Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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24 h
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Applications
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CCT129202 inhibited proliferation in multiple cultures of human tumor cell lines with half-maximal growth inhibition (GI50) values ranging from 0.08 μM for MV4-11 to 1.7 μM for MDA-MB-157. Treatment with CCT129202 (0.7 μM) caused the accumulation of HCT116 cells with ≥4N DNA content, leading to apoptosis in a time dependent manner. Application of CCT129202 in HCT116 cells decreased histone H3 phosphorylation and increased p53 protein stabilization. CCT129202 induced up-regulation of p21 in HCT116, HT29 and Hela cells in a p53 dependent and independent manner. CCT129202 decreased phosphorylation of the Rb protein and activity of E2F in a concentration-dependent manner.
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Animal experiment [1]:
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Animal models
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Female NCr athymic mice human HCT116 colon carcinoma xenografts
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Dosage form
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Intraperitoneal injection, 100 mg/kg
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Application
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Administration of CCT129202 at 100 mg/kg in athymic mice bearing s.c. HCT116 colon cancer xenografts causes ~50% reduction of histone H3 phosphorylation after 30 minutes of treatment, and significantly inhibited tumor growth by 57.7% compared to control mice after a period of 9 days of treatment.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Chan F, Sun C, Perumal M, et al. Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity[J]. Molecular Cancer Therapeutics, 2007, 6(12): 3147-3157.
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