Structure-Based Design of Spiro-oxindoles as Potent, Specific Small-Molecule Inhibitors of the MDM2−p53 Interaction
Abstract
Potent, specific, non-peptide small-molecule inhibitors of the MDM2-p53 interaction were successfully designed. The most potent inhibitor (MI-63) has a K(i) value of 3 nM binding to MDM2 and greater than 10,000-fold selectivity over Bcl-2/Bcl-xL proteins. MI-63 is highly effective in activation of p53 function and in inhibition of cell growth in cancer cells with wild-type p53 status. MI-63 has excellent specificity over cancer cells with deleted p53 and shows a minimal toxicity to normal cells.
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Small-molecule PPI antagonists that disrupt the p53-MDM2 interaction have been identified, including nutlin 3a and MI-219.
“Small-molecule PPI antagonists that disrupt the p53–MDM2 interaction have been identified, including nutlin 3a96 and MI-219 (Ref. 97).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [97]
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- Authors
- Ding, K., Lu, Y., Nikolovska-Coleska, Z., Wang, G., Qiu, S., Shangary, S., Gao, W., Qin, D., Stuckey, J., Krajewski, K., Roller, P. P., & Wang, S.
- Affiliations
- National Institutes of Health (US)
- Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, and Life Sciences Institute, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, and Laboratory of Medicinal Chemistry, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-05-13
- Volume
- 49
- Issue
- 12
- Pages
- 3432-3435
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2022416218
- Cited by
- 702
- References
- 20
- Citations by year
- 2026: 19 · 2025: 26 · 2024: 23 · 2023: 23 · 2022: 27 · 2021: 40 · 2020: 32 · 2019: 28 · 2018: 37 · 2017: 35 · 2016: 43 · 2015: 53 · 2014: 67 · 2013: 52 · 2012: 52
- FWCI
- 12.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P50CA097248, R01CA121279, P50CA069568, P30CA046592)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- p53-MDM2 interaction, small molecule inhibitors, spirooxindoles, p53 activation, structure-based drug design, tumor cell growth inhibition, non-peptidic inhibitors
- MeSH terms
- Antineoplastic Agents, Cell Membrane Permeability, Drug Screening Assays, Antitumor, Humans, Indoles, Models, Molecular, Protein Binding, Spiro Compounds, Structure-Activity Relationship, Tumor Suppressor Protein p53, Crystallography, X-Ray, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2
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