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Evaluation of a multi-kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo

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Summary

Kinases have been studied as potential cancer targets because they play important roles in the cellular signaling of tumors. A number of small molecules targeting kinases are prescribed in clinics and many kinase inhibitors are being evaluated in the clinical phase. Previously, we discovered a series of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors. One of the compounds, KRC-108, has been evaluated as an anti-cancer agent in vitro and in vivo. A kinase panel assay exhibited that KRC-108 is a potent inhibitor of Ron, Flt3 and TrkA as well as c-Met. Moreover, KRC-108 inhibited oncogenic c-Met M1250T and Y1230D more strongly than wild type c-Met. The anti-proliferative activity of KRC-108 was measured by performing a cytotoxicity assay on a panel of cancer cell lines. The GI50 values (i.e., 50% inhibition of cell growth) for KRC-108 ranged from 0.01 to 4.22 μM for these cancer cell lines. KRC-108 was also effective for the inhibition of tumor growth in human HT29 colorectal cancer and NCI-H441 lung cancer xenograft models in athymic BALB/c nu/nu mice. This molecule should serve as a useful lead for inhibitors targeting kinases and may lead to new therapeutics for the treatment of cancer.

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Abbreviations

HTRF:

Homogeneous time-resolved fluorescence

EGFR:

Epidermal growth factor receptor

IGF1R:

Insulin-like growth factor 1 receptor

IR:

Insulin receptor

ALK:

Anaplastic lymphoma kinase

VEGFR2:

Vascular endothelial growth factor receptor 2

CYP450:

Cytochrome P450

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Acknowledgments

This work was supported by the Korea Research Institute of Chemical Technology (KRICT) and the National Research Foundation of Korea (NRF) Grant (J.L., R01-2008-000-20205-0) funded by the government of Korea (MEST), and partially by a grant of the Korea Healthcare Technology R&D Project (S.-Y.H., A100096) funded by the government of Korea (MHWFA). We thank the Drug Discovery Technology Platform team at KRICT and the U. S. National Cancer Institute Developmental Therapeutics Program (NCI-DTP) for providing us with technical assistance on the experiments and for performing the cytotoxicity assay of KRC-108 against NCI-60 cell lines, respectively.

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Authors and Affiliations

  1. Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon, 305-600, Korea

    Sun-Young Han, Chong Ock Lee, Sung-Hoon Ahn, Sung Yun Cho, Jae Du Ha, Jae Wook Ryu, Heejung Jung, Hyoung Rae Kim, Jong Sung Koh & Jongkook Lee

  2. Department of Biomedical Science, College of Life Science, CHA University, Pochon-si, Gyeonggi-do, 487-801, Korea

    Mi-Ok Lee, So-Young Kang & Hyuk-Jin Cha

  3. Stem Cell Research Laboratory, CHA Stem Cell Institute, CHA University, Seoul, 135-907, Korea

    Mi-Ok Lee, So-Young Kang & Hyuk-Jin Cha

  4. College of Pharmacy and Institute of Health Sciences, Gyeongsang National University, Jinju, 660-751, Korea

    Sun-Young Han

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  1. Sun-Young Han
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Correspondence to Jongkook Lee.

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Han, SY., Lee, C.O., Ahn, SH. et al. Evaluation of a multi-kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo. Invest New Drugs 30, 518–523 (2012). https://doi.org/10.1007/s10637-010-9584-2

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  • DOI: https://doi.org/10.1007/s10637-010-9584-2

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