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A Small Molecule Inhibits Protein Disulfide Isomerase and Triggers the Chemosensitization of Cancer Cells |
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| Authors: | Dr. Jürgen Eirich Dr. Simone Braig Dr. Liliana Schyschka Phil Servatius Judith Hoffmann Sabrina Hecht Prof. Dr. Simone Fulda Prof. Dr. Stefan Zahler Prof. Dr. Iris Antes Prof. Dr. Uli Kazmaier Prof. Dr. Stephan A. Sieber Prof. Dr. Angelika M. Vollmar |
| Affiliation: | 1. Center for Integrated Protein Science Munich CIPSM, Department of Chemistry, Institute of Advanced Studies IAS, Technische Universit?t München, Lichtenbergstrasse 4, 85747 Garching (Germany);2. Current address: Department of Oncology/Pathology, Cancer Proteomics Mass Spectrometry, SciLifeLab Stockholm, Karolinska Institutet, Tomtebodav?gen 23, 17165 Solna (Sweden);3. Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, Ludwig‐Maximilians‐Universit?t München, Butenandtstrasse 5–13, 81377 München (Germany);4. Institute for Organic Chemistry, Saarland University, Im Stadtwald, Geb. C4.2, 66123 Saarbrücken (Germany);5. Department of Life Sciences, Technische Universit?t München, Emil‐Erlenmeyer‐Forum 8, 85354 Freising‐Weihenstephan (Germany);6. Institute for Experimental Cancer Research in Pediatrics, University Hospital Frankfurt, Komturstrasse 3a, 60528 Frankfurt a.?M. (Germany) |
| Abstract: | 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. |
| Keywords: | cancer chemotherapeutics combination therapy proteomics sensitization |