Research

A series of novel imidazo heterocycle compounds was synthesized by the SHEN JingKang’s group through using combinatorial methodologies. Researchers from the groups of SHEN JingKang , DING Jian and MIAO Zehong have demonstrated the anticancer anctivities, target and cellular and molecular mechanisms of these compounds and established their structure-activity relationships [Invest New Drug. 2010;28(6):715-28；Int J Cancer. 2011; 129(1):214-24；Bioorg Med Chem. 2014; 22:848-55；Mol Cancer Ther. 2014;13(6); 1480-91].

As an early representative compound of this series, MT7 shows its non-selective in vitro antiproliferative activity against 12 tumor cell lines with an averaged IC50 of 2.58 mM ranging from 0.85 mM to 5.01 mM. MT7 induces specific, reversible mitotic arrest in tumor cells and leads to the mitotic arrest-associated changes in the gene expression profile in HeLa cells. MT7 inhibits the polymerization of cellular microtubules, and thus disrupts spindle assembly and activates the spindle assembly checkpoint; it does not affect the mitotic regulators other than tubulin. MT7 neither intercalates into DNA, nor inhibits topoisomerase activities. These data suggest that MT7 is likely a microtubulin inhibitor [Invest New Drug. 2010;28(6):715-28]. Disappointingly, however, MT7 does not display microtubulin inhibitory activity in cell-free systems, possibly due to its relatively weak efficacy. Therefore, MT119, a new derivative of MT7 with greatly improved in vitro antiproliferative activity (the averaged IC50 of 0.34 mM ranging from 0.06 mM to 0.53 mM in a panel of 10 tumor cell lines), was selected to further demonstrate the anticancer target of this series. The result shows that MT119 directly inhibits the polymerization of microtubulin by binding to its colchicine site and causes similar but more potent cellular effects than MT7, confirming that microtubulin is the anticancer target of the tested compounds [Int J Cancer. 2011; 129(1):214-24].

To further clarify the cellular and molecular mechanisms of action, MT189, a new derivative of MT189 with further improved in vitro antiproliferative activity (the averaged IC50 of 0.1 mM ranging from 0.01 mM to 0.3 mM in a panel of 14 tumor cell lines), was chosen. MT189 was revealed to elicit its anticancer activity by inhibiting microtubulin polymerization, leading to persistent mitotic arrest and inducing apoptosis. Moreover, its anticancer activity is further potentiated by relieving the apoptotic inhibition of the antiapoptotic protein MCL-1 due to its degradation driven by the JNK-mediated phosphorylation via the MEKK1/TAK1-MKK4 pathway [Mol Cancer Ther. 2014;13(6); 1480-91]. Based on the above findings, the structure-activity relationships of this series have been established [Bioorg Med Chem. 2014; 22:848-55], laying a solid basis for the future R & D work on this type of compounds.

In addition, we have also done a lot of other work about this series of compounds, including evaluating their in vivo anticancer activity and pharmacokinetics. Disappointingly, however, their in vivo anticancer activity did not increase as their in vitro antiproliferative activity did. And even when their concentrations in the xenografts in nude mice reached or were higher than the effective concentrations in their in vitro antiproliferative experiments, their in vivo anticancer activity was still poor. These experiences suggest that there are a lot of unknown but critical factors in the R & D process of anticancer drugs, which remains to be explored continuously.

1. Zhixiang Zhang, Tao Meng, Jingxue He, Ming Li, Lin-Jiang Tong, Bing Xiong, Liping Lin, Jingkang Shen, Ze-Hong Miao* and Jian Ding*. MT7, a novel compound from a combinatorial library, arrests mitosis via inhibiting the polymerization of microtubules. Invest New Drug. 2010;28(6):715-28.

2. Zhixiang Zhang, Tao Meng, Na Yang, Wei Wang, Bing Xiong, Yi Chen, Lanping Ma, Jingkang Shen, Ze-Hong Miao*, Jian Ding*. MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation. Int J Cancer. 2011; 129(1):214-24

3. Tao Meng, Wei Wang, Zhixiang Zhang, Lanping Ma*, Yongliang Zhang, Zehong Miao*, Jingkang Shen*. Synthesis and biological evaluation of 6H-pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5 (6H)-ones as antimitotic agents and inhibitors of tubulin polymerization. Bioorg Med Chem. 2014; 22:848-55.

4. Wei Wang, Ying-Qing Wang, Tao Meng, Jun-Mei Yi, Xia-Juan Huan, Lan-Ping Ma, Lin-Jiang Tong, Yi Chen, Jian Ding, Jing-Kang Shen*, Ze-Hong Miao*. MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189. Mol Cancer Ther. 2014;13(6); 1480-91.

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