1. A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction
- Author
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Justyna Kalinowska-Tluscik, Bogdan Musielak, Katarzyna Kubica, Jan Potempa, Mateusz Jabłoński, Tad A. Holak, Grzegorz Dubin, Marcin Tomala, Krzysztof M. Zak, Aleksandra Twarda-Clapa, Mariusz Madej, Przemyslaw Grudnik, Ewa Surmiak, Alexander Dömling, Drug Design, and Medicinal Chemistry and Bioanalysis (MCB)
- Subjects
Models, Molecular ,0301 basic medicine ,STRUCTURE-BASED DESIGN ,CANCER-THERAPY ,MDMX ,Protein Conformation ,Stereochemistry ,Crystallography, X-Ray ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Protein–protein interaction ,Structure-Activity Relationship ,PROTEIN-PROTEIN INTERACTIONS ,03 medical and health sciences ,4-Butyrolactone ,Humans ,Pyrroles ,Protein Interaction Maps ,neoplasms ,MDM2-P53 INTERACTION ,chemistry.chemical_classification ,DNA ligase ,POTENT ,Chemistry ,Drug discovery ,Proto-Oncogene Proteins c-mdm2 ,General Medicine ,TUMOR-SUPPRESSOR P53 ,Small molecule ,0104 chemical sciences ,DRUG DISCOVERY ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,Drug Design ,NMR-SPECTROSCOPY ,LIGAND-BINDING ,Molecular Medicine ,SMALL-MOLECULE INHIBITORS ,Protein Multimerization ,Tumor Suppressor Protein p53 ,Pharmacophore ,Heteronuclear single quantum coherence spectroscopy ,Function (biology) - Abstract
The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.
- Published
- 2016
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