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Understanding small-molecule binding to MDM2: insights into structural effects of isoindolinone inhibitors from NMR spectroscopy.
- Source :
-
Chemical biology & drug design [Chem Biol Drug Des] 2011 May; Vol. 77 (5), pp. 301-8. Date of Electronic Publication: 2011 Mar 01. - Publication Year :
- 2011
-
Abstract
- The interaction between murine double minute (MDM2) and p53 is a major target in anticancer drug design. Several potent compound series, including the nutlins and spirooxindoles, have previously been established as high-affinity antagonists of MDM2. In this paper, we describe the interaction of isoindolinone inhibitors with MDM2, as characterized by nuclear magnetic resonance spectroscopy. Isoindolinone inhibitors bind specifically to the MDM2 p53 binding site and exploit all sub-pockets used by p53, nutlins and spirooxindoles. Furthermore, isoindolinones bind with low micromolar to high nanomolar affinities, with the best compound approaching the potency of nutlin-3.<br /> (© 2011 John Wiley & Sons A/S.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Binding, Competitive drug effects
Cell Line, Tumor
Cloning, Molecular
Enzyme Inhibitors pharmacology
Escherichia coli
Humans
Imidazoles pharmacology
Kinetics
Magnetic Resonance Spectroscopy
Mice
Models, Molecular
Piperazines pharmacology
Protein Binding drug effects
Proto-Oncogene Proteins c-mdm2 genetics
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Small Molecule Libraries pharmacology
Tumor Suppressor Protein p53 genetics
Isoindoles pharmacology
Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 chemistry
Recombinant Fusion Proteins chemistry
Tumor Suppressor Protein p53 chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1747-0285
- Volume :
- 77
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Chemical biology & drug design
- Publication Type :
- Academic Journal
- Accession number :
- 21244642
- Full Text :
- https://doi.org/10.1111/j.1747-0285.2011.01091.x