Erschienen in:
01.04.2012 | PRECLINICAL STUDIES
Evaluation of a multi-kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo
verfasst von:
Sun-Young Han, Chong Ock Lee, Sung-Hoon Ahn, Mi-Ok Lee, So-Young Kang, Hyuk-Jin Cha, Sung Yun Cho, Jae Du Ha, Jae Wook Ryu, Heejung Jung, Hyoung Rae Kim, Jong Sung Koh, Jongkook Lee
Erschienen in:
Investigational New Drugs
|
Ausgabe 2/2012
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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.