期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 53, 期 47, 页码 12960-12965出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201406577
关键词
cancer; chemotherapeutics; combination therapy; proteomics; sensitization
资金
- Deutsche Forschungsgemeinschaft [SFB749, SFB1035, FOR1406]
- ERC
- Center for Integrated Protein Science Munich CIPSM
- TUM Graduate School
- Wilhelm Sander Foundation
Resistance to chemotherapeutic agents represents a major challenge in cancer research. One approach to this problem is combination therapy, the application of a toxic chemotherapeutic drug together with a sensitizing compound that addresses the vulnerability of cancer cells to induce apoptosis. Here we report the discovery of a new compound class (T8) that sensitizes various cancer cells towards etoposide treatment at subtoxic concentrations. Proteomic analysis revealed protein disulfide isomerase (PDI) as the target of the T8 class. In-depth chemical and biological studies such as the synthesis of optimized compounds, molecular docking analyses, cellular imaging, and apoptosis assays confirmed the unique mode of action through reversible PDI inhibition.
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