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Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties

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Summary

Through rational drug design, we previously identified an indenoprazole derivative, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide (LL01), as a potent tubulin polymerization inhibitor targeting the tubulin colchicine binding site. In this study, we further demonstrated that LL01 was not a P-gp substrate. It potently inhibited the growth of a variety of tumor cells, including those with multidrug resistance, with GI50 values in the low nanomole ranges. In vitro liver microsome stability assay, LL01 was modest stable in the liver microsomes of human, mouse and rat, but was fast metabolized in dog. After single oral administration of LL01 at a dose of 10 mg/kg in SD male rats, LL01 showed acceptable PK properties with a mean bioavailability of 41%. In human HepG2 hepatoma xenograft, at the oral doses of 25 mg/kg/day and 12.5 mg/kg/day, LL01 inhibited the tumor growth by 61.27%, and 43.74%, respectively, which is much better than the positive drug sorafenib (29.45%; 30 mg/kg/day). Therefore, LL01 might be a potential drug candidate for further investigation for hepatocellular carcinoma therapy.

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Funding

The work was supported by the National Natural Science Foundation of China (NSFC, Grant No. 81573275) and the Key Research and Development Project of Shandong Province (2017CXGC1401), China.

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Authors and Affiliations

  1. Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China

    Jing-De Wu, Ying-Jie Cui, Long-Qian Tang, Cheng-Mei Zhang & Zhao-Peng Liu

  2. Actpharma Co. Ltd., Shanghe Economic Development Zone of Shandong Province, Shanghe, 251600, China

    Yi-Gang Zhou

Authors
  1. Jing-De Wu
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  2. Ying-Jie Cui
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  3. Yi-Gang Zhou
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  4. Long-Qian Tang
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  5. Cheng-Mei Zhang
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  6. Zhao-Peng Liu
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Contributions

All authors contributed substantially to the study. Data were generated and analysed by JDW, YJC, YGZ, LQT, CMZ and ZPL. YJC, YGZ, LQT and CMZ contributed to the design of some of the studies and interpretation of results. JDW, YGZ and ZPL designed the overall study, interpreted all results. JDW wrote the manuscript and ZPL made a revision. All authors reviewed the manuscript for accuracy and contributed to the writing of the manuscript.

Corresponding author

Correspondence to Zhao-Peng Liu.

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Conflict of interest

Author JDW declares that he has no conflict of interest. Author YJC declares that he has no conflict of interest. Author YGZ declares that he has no conflict of interest. Author LQT declares that he has no conflict of interest. Author CMZ declares that she has no conflict of interest. Author ZPL declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants. The animal experiments were performed under the guidance of the Animal Care and Welfare Committee of Shandong University and followed the principles outlined in the Declaration of Helsinki for animal experimental investigations.

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Informed consent was obtained from all individual participants included in the study.

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Wu, JD., Cui, YJ., Zhou, YG. et al. Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties. Invest New Drugs 38, 29–38 (2020). https://doi.org/10.1007/s10637-019-00753-z

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  • DOI: https://doi.org/10.1007/s10637-019-00753-z

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