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Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2011 Mar 10; Vol. 54 (5), pp. 1233-43. Date of Electronic Publication: 2011 Feb 11. - Publication Year :
- 2011
-
Abstract
- Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 ± 0.01 μM). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC(50) = 0.17 ± 0.02 μM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.
- Subjects :
- Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Cell Line, Tumor
Cell Proliferation drug effects
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Humans
Isoindoles chemistry
Isoindoles pharmacology
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Structure
Protein Binding
Stereoisomerism
Structure-Activity Relationship
Antineoplastic Agents chemical synthesis
Isoindoles chemical synthesis
Proto-Oncogene Proteins c-mdm2 metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 54
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21314128
- Full Text :
- https://doi.org/10.1021/jm1011929