- A small molecule inhibits protein disulfide isomerase and triggers the chemosensitization of cancer cells
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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. In the battle against the chemoresistance of cancer cells a screening approach has identified a novel compound class that sensitizes cancer cells in combination with etoposide. Proteomic target discovery revealed the reversible inhibition of protein disulfide isomerase as the molecular mechanism, which was further supported by cellular imaging studies and docking and biochemical assays in various cancer model systems.
- 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.
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supporting information
p. 12960 - 12965
(2016/02/18)
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- Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity
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When the dialkylacetamide side chain of the ETA-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ETB over ETA. By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ETB and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ETB receptor in modulating blood pressure; the observed hypertensive response to persistent ETB blockade is consistent with previous postulates and indicates that ETB-selective antagonists may not be suitable as agents for long-term systemic therapy.
- Von Geldern, Thomas W.,Tasker, Andrew S.,Sorensen, Bryan K.,Winn, Martin,Szczepankiewicz, Bruce G.,Dixon, Douglas B.,Chiou, William J.,Wang, Liming,Wessale, Jerry L.,Adler, Andy,Marsh, Kennan C.,Nguyen, Bach,Opgenorth, Terry J.
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p. 3668 - 3678
(2007/10/03)
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