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A Small Molecule Inhibits Protein Disulfide Isomerase and Triggers the Chemosensitization of Cancer Cells
Author(s) -
Eirich Jürgen,
Braig Simone,
Schyschka Liliana,
Servatius Phil,
Hoffmann Judith,
Hecht Sabrina,
Fulda Simone,
Zahler Stefan,
Antes Iris,
Kazmaier Uli,
Sieber Stephan A.,
Vollmar Angelika M.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201406577
Subject(s) - protein disulfide isomerase , cancer cell , chemistry , apoptosis , small molecule , etoposide , mode of action , isomerase , biochemistry , drug discovery , cancer research , cancer , disulfide bond , biology , enzyme , chemotherapy , genetics
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.