| Breast cancer is ranked as the leading threaten to women, and its metastasis incurs patients’mortality in clinic. To develop treatment for tumor carcinogenesis, we demonstrated that KHS101, a small molecule, has anti-tumor effects in several cell lines with overexpression of Transforming Acidic Coiled-coil (TACC3) and anti-angiogenesis function. In an attempt to develop more effective drugs, we chemically modified KHS101 and screened for the effects of resultant derivatives in several cancer cell lines. To our delight, we discovered that ZY-444, a novel compound, possessed the strongest anti-breast cancer proliferation and metastasis activity in vitro. In addition, we confirmed that ZY-444 conferred 100 times less toxicity to normal epithelial cells, and illustrated that this chemical induced cancer cell apoptosis and cell cycle arrest. Furthermore, we continued to analyze the effects of the compound on breast cancer proliferation, metastasis and recurrence in six metastatic animal models,4T1 and MDA-MB-231 spontaneous metastasis models, MDA-MB-231 intravenous experimental metastasis models,4T1 recurrence model and acute toxicity model included. Our data on these animal models also pointed out that, to some extent, ZY-444 was more effective and at the same time it might be less toxic than paclitaxel, a common anti-microtubule agent, suggesting ZY-444’s promising potential for breast cancer treatment.Given the positive hit, we continued to explore the mechanism by which this drug acts on cells. Kinase assays disproved ZY-444 as an Aurora A Kinase even though its chemical structure similar with clinical Aurora Kinase inhibitors. Also, our data including TACC3 knockdown and immunoflurescence assay does not fully substantiate that ZY-444 is specially binding to TACC3 in human cancer cell lines. Till now, we have synthesed biotin-conjugated ZY-444 with biogical activity. At last, biotin-assisted pulldown assay will help us unveil its direct and specific target. |
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