期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 24, 期 1, 页码 126-131出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.11.064
关键词
Human epidermal growth factor receptor 2 (HER2); HER2 Delta 16; Tyrosine kinase; Emodin; Quinones; Phosphorylation; Breast cancer; Docking studies
资金
- Department of Defense [W81XWH-11-1-0105]
- NIH-RCMI from the National Institute on Minority Health and Health Disparities [8G12MD007595-04]
HER2 overexpression is associated with aggressive breast cancer with high recurrence rate and poor patient prognosis. Treatment of HER2 overexpressing patients with the HER2 targeting therapy trastuzumab results in acquired resistance within a year. The HER2/EGFR dual kinase inhibitor lapatinib was shown to inhibit some trastuzumab resistant breast cancer cell lines and is currently in clinical trials. Our group has found two new quinone compounds that show excellent inhibition of breast tumor cells expressing HER2 or the trastuzumab resistant HER2 oncogenic isoform, HER2 Delta 16. Compound 4 ((1R,2S,3S)-1,2,3,5,8-pentahydroxy-1,2,3,4-tetrahydroanthracene-9,10-dione) and compound 5 (5,8-dihydroxy-2,3-bis(hydroxymethyl)naphthalene-1,4-dione) showed sub-micromolar inhibition potency against these cell lines. These compounds also inhibit auto-phosphorylation of the Y1248 and Y1068 residues of HER2 and EGFR, respectively. (C) 2013 Elsevier Ltd. All rights reserved.
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