Isoquinolin‐1‐one Inhibitors of the MDM2–p53 Interaction
| Autor: | Anna Czarna, Günther Ross, Lutz Weber, Natalia Skobeleva, Cedric Kalinski, Tad A. Holak, Marcin Krajewski, Jolanta Ciombor, Vladimir Khazak, Ulli Rothweiler |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Protein Folding
Magnetic Resonance Spectroscopy In silico Antineoplastic Agents Apoptosis Biochemistry Protein–protein interaction Inhibitory Concentration 50 Cell Line Tumor Drug Discovery Humans Computer Simulation Mdm2 p53 Enzyme Inhibitors General Pharmacology Toxicology and Pharmaceutics Cell Proliferation Pharmacology Chemistry Organic Chemistry Proto-Oncogene Proteins c-mdm2 Isoquinolines Combinatorial chemistry In vitro Drug Design Molecular Medicine Protein Binding |
| Zdroj: | ChemMedChem. 3:1118-1128 |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | p53 has been at the centre of attention for drug design since the discovery of its growth-suppressive and pro-apoptotic activity. Herein we report the design and characterisation of a new class of isoquinolinone inhibitors of the MDM2-p53 interaction. Our identification of druglike and selective inhibitors of this protein-protein interaction included a straightforward in silico compound-selection process, a recently reported NMR spectroscopic approach for studying the MDM2-p53 interaction, and selectivity screening assays using cells with the same genetic background. The selected inhibitors were all able to induce apoptosis and the expression of p53-related genes, but only the isoquinolin-1-one-based inhibitors stabilised p53. Our NMR experiments give a persuading explanation for these results, showing that isoquinolin-1-one derivates are able to dissociate the preformed MDM2-p53 complex in vitro, releasing a folded and soluble p53. The joint application of these methods provides a framework for the discovery of protein interaction inhibitors as a promising starting point for further drug design. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text