title: A small molecule inhibits protein disulfide isomerase and triggers the chemosensitization of cancer cells.
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.
authors.affiliation: Center for Integrated Protein Science Munich CIPSM, Department of Chemistry, Institute of Advanced Studies IAS, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany); Current address: Department of Oncology/Pathology, Cancer Proteomics Mass Spectrometry, SciLifeLab Stockholm, Karolinska Institutet, Tomtebodavägen 23, 17165 Solna (Sweden).
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eirich
authors.forename: Simone
authors.initials: S
authors.lastname: Braig
authors.forename: Liliana
authors.initials: L
authors.lastname: Schyschka
authors.forename: Phil
authors.initials: P
authors.lastname: Servatius
authors.forename: Judith
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Sabrina
authors.initials: S
authors.lastname: Hecht
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.forename: Iris
authors.initials: I
authors.lastname: Antes
authors.forename: Uli
authors.initials: U
authors.lastname: Kazmaier
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040901:Proteomics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D019704:Protein Disulfide-Isomerases
keywords: cancer; chemotherapeutics; combination therapy; proteomics; sensitization