CCT129202

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

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.

Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity.[Pubmed:18089709]

Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3147-57.

The Aurora family of serine/threonine kinases is important for the regulation of centrosome maturation, chromosome segregation, and cytokinesis during mitosis. Overexpression of Aurora kinases in mammalian cells leads to genetic instability and transformation. Increased levels of Aurora kinases have also been linked to a broad range of human tumors. Here, we describe the properties of CCT129202, a representative of a structurally novel series of imidazopyridine small-molecule inhibitors of Aurora kinase activity. This compound showed high selectivity for the Aurora kinases over a panel of other kinases tested and inhibits proliferation in multiple cultured human tumor cell lines. CCT129202 causes the accumulation of human tumor cells with >or=4N DNA content, leading to apoptosis. CCT120202-treated human tumor cells showed a delay in mitosis, abrogation of nocodazole-induced mitotic arrest, and spindle defects. Growth of HCT116 xenografts in nude mice was inhibited after i.p. administration of CCT129202. We show that p21, the cyclin-dependent kinase inhibitor, is induced by CCT129202. Up-regulation of p21 by CCT129202 in HCT116 cells led to Rb hypophosphorylation and E2F inhibition, contributing to a decrease in thymidine kinase 1 transcription. This has facilitated the use of 3'-deoxy-3'[(18)F]fluorothymidine-positron emission tomography to measure noninvasively the biological activity of the Aurora kinase inhibitor CCT129202 in vivo.

Protein kinase C modulates Aurora-kinase inhibition induced by CCT129202 in HMC-1(5)(6)(0),(8)(1)(6) cell line.[Pubmed:23701310]

Antiinflamm Antiallergy Agents Med Chem. 2013;12(3):265-76.

The human mast cell line HMC-1(5)(6)(0),(8)(1)(6) carries activating mutations in the proto-oncogene of c-kit that cause autophosphorylation and permanent c-kit receptor activation. The compound CCT129202 is a new and selective inhibitor of Aurora kinase A and B that decreases the viability of a variety of human tumor cell lines. The effect of Aurora kinase inhibition was assessed in the HMC-1(5)(6)(0),(8)(1)(6) line in order to find a suitable tool for mastocytosis treatment. CCT129202 treatment induces a significant decrease in cell viability in HMC-1(5)(6)(0),(8)(1)(6) cells after 48 hours of treatment. Moreover, caspase-3 and caspase-8 activation was induced after incubation of HMC-1(5)(6)(0),(8)(1)(6) cells in the presence of CCT129202. It has been demonstrated that Protein Kinase C (PKC) plays a crucial role in mast cell activation as well as cell migration, adhesion and apoptotic cell death. Co-treatment of Ca(2)(+)-independent PKCs (delta epsilon and theta) inhibitor GF109203X with CCT129202, reduces caspase-3 activation which controls cell levels. In contrast, Go6976, an inhibitor of Ca(2)(+)-dependent PKCs, increases caspase-3 activation. Oppositely, GF109203X does not modify CCT129202-induced apoptosis through the caspase-8 pathway whereas Go6976 treatment abolishes the increase on caspase-8 activity due to CCT129202. This implies that Ca(2)(+)-independent PKC isoforms seems to be related with CCT129202-induced apoptosis through the caspase- 3 pathway, whereas Ca(2)(+)-dependent PKC isoforms are related with the CCT129202 effect on the caspase-8 pathway. Interestingly, CCT129202 cytotoxic effect remains even though Ca(2)(+)-dependent PKCs are inhibited, which shows that the Aurora kinase inhibitor effect is acting through the caspase-3 pathway. On the other hand, Ca(2)(+)-independent PKCs inhibition does not affect the final apoptotic CCT129202 effect because this seems to be mediated by the caspase-8 pathway. Moreover, CCT129202 does not affect PKCdelta and Ca(2)(+)-dependent PKC translocation, which indicates that PKC translocation pivots on its activation. This demonstrates that Aurora kinase inhibition is not related to this process. Finally, when PKC is silenced in HMC-1(5)(6)(0),(8)(1)(6) cells, the effect of CCT129202 on the caspase-3 pathway disappears, which indicates that the CCT129202 effect is clearly PKC-dependent.

Enhancing chemosensitivity in ABCB1- and ABCG2-overexpressing cells and cancer stem-like cells by an Aurora kinase inhibitor CCT129202.[Pubmed:22632055]

Mol Pharm. 2012 Jul 2;9(7):1971-82.

Imidazopyridine CCT129202 is an inhibitor of Aurora kinase activity and displays a favorable antineoplastic effect in preclinical studies. Here, we investigated the enhanced effect of CCT129202 on the cytotoxicity of chemotherapeutic drugs in multidrug resistant (MDR) cells with overexpression of ATP-binding cassette (ABC) transporters and cancer stem-like cells. CCT129202 of more than 90% cell survival concentration significantly enhanced the cytotoxicity of substrate drugs and increased the intracellular accumulations of doxorubicin and rhodamine 123 in ABCB1 and ABCG2 overexpressing cells, while no effect was found on parental sensitive cells. Interestingly, CCT129202 also potentiated the sensitivity of cancer stem-like cells to doxorubicin. Importantly, CCT129202 increased the inhibitory effect of vincristine and paclitaxel on ABCB1 overexpressing KBv200 cell xenografts in nude mice and human esophageal cancer tissue overexpressing ABCB1 ex vivo, respectively. Furthermore, the ATPase activity of ABCB1 was inhibited by CCT129202. Homology modeling predicted the binding conformation of CCT129202 within the large hydrophobic cavity of ABCB1. On the other hand, CCT129202 neither apparently altered the expression levels of ABCB1 and ABCG2 nor inhibited the activity of Aurora kinases in MDR cells under the concentration of reversal MDR. In conclusion, CCT129202 significantly reversed ABCB1- and ABCG2-mediated MDR in vitro, in vivo and ex vivo by inhibiting the function of their transporters and enhanced the eradication of cancer stem-like cells by chemotherapeutic agents. CCT129202 may be a candidate as MDR reversal agent for antineoplastic combination therapy and merits further clinical investigation.