Proteomimetic Libraries: Design, Synthesis, and Evaluation of p53−MDM2 Interaction Inhibitors
- 15 March 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Combinatorial Chemistry
- Vol. 8 (3) , 315-325
- https://doi.org/10.1021/cc050142v
Abstract
The p53−MDM2 interaction regulates p53-mediated cellular responses to DNA damage, and MDM2 is overexpressed in 7% of all cancers. Structure-based computational design was applied to this system to design libraries centered on a scaffold that projects side chain functionalities with distance and angular relationships equivalent to those seen in the MDM2 interacting motif of p53. A library of 173 such compounds was synthesized using solution phase parallel chemistry. The in vitro competitive ability of the compounds to block p53 peptide binding to MDM2 was determined using a fluorescence polarization competition assay. The most active compound bound with Kd = 12 μM, and its binding was characterized by 15N-1H HSQC NMR.Keywords
This publication has 32 references indexed in Scilit:
- Discovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists That Activate p53 in CellsJournal of Medicinal Chemistry, 2005
- Isoindolinone-based inhibitors of the MDM2–p53 protein–protein interactionBioorganic & Medicinal Chemistry Letters, 2005
- Emerging classes of protein–protein interaction inhibitors and new tools for their developmentCurrent Opinion in Chemical Biology, 2004
- Fluorescence polarization assay and inhibitor design for MDM2/p53 interactionAnalytical Biochemistry, 2004
- A Nonpeptidic Sulfonamide Inhibits the p53−mdm2 Interaction and Activates p53-Dependent Transcription in mdm2-Overexpressing CellsJournal of Medicinal Chemistry, 2004
- Improved Synthesis of Proline-Derived Ni(II) Complexes of Glycine: Versatile Chiral Equivalents of Nucleophilic Glycine for General Asymmetric Synthesis of α-Amino AcidsThe Journal of Organic Chemistry, 2003
- Design of a Protein Surface Antagonist Based on α-Helix Mimicry: Inhibition of gp41 Assembly and Viral Fusion We thank the National Institutes of Health for support of this work and the Deutsche Forschungsgemeinschaft (DFG) for a research fellowship to O.K.Angewandte Chemie International Edition in English, 2002
- Anatomy of hot spots in protein interfacesJournal of Molecular Biology, 1998
- Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation DomainScience, 1996
- DERIVATIVES OF PHENYLBORIC ACID, THEIR PREPARATION AND ACTION UPON BACTERIAJournal of the American Chemical Society, 1931