Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay
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Abstract
E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Overexpression of Mdm2 facilitates tumorigenesis by inactivating p53, and through p53-independent oncogenic effects. We developed a high-throughput cellular Mdm2 auto-ubiquitination assay, which we used to discover a class of small-molecule Mdm2 ligase activity inhibitors. These compounds inhibit Mdm2 and p53 ubiquitination in cells, reduce viability of cells with wild-type p53, and synergize with DNA-damaging agents to cause cell death. We determined that these compounds effectively inhibit the E3 ligase activity of the Mdm2-MdmX hetero-complex. This mechanism may be exploitable to create a new class of anti-tumor agents. Significance: We identified a class of small-molecule inhibitors of the Mdm2-MdmX hetero-complex E3 ligase activity through a high-throughput cell-based Mdm2 ubiquitination screen. This is a new target for small-molecule therapeutics and may be developed to treat specific cancers. Cancer Discovery; 1(4); 312–25. ©2011 AACR. This article is highlighted in the In This Issue feature, p. 275
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Several compounds that block MDM2's ubiquitin ligase function were found in high-throughput screens, such as HLI98, MPD derivatives, MEL23 and MEL24.
“Small molecules that inhibit MDM2 ubiquitin ligase activity have been identified in high-throughput screens. These include HLI98 (Ref. 115), the derivative MPD compounds116, MEL23 and MEL24 (Ref. 117).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [117]
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- Authors
- Herman, A. G., Hayano, M., Poyurovsky, M. V., Shimada, K., Skouta, R., Prives, C., & Stockwell, B. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Stockwell, Brent R.
- Venue
- Cancer Discovery
- Published
- 2011-09-01
- Volume
- 1
- Issue
- 4
- Pages
- 312-325
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3353153
- OpenAlex
- W2116565198
- Cited by
- 100
- References
- 57
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 6 · 2023: 3 · 2022: 7 · 2021: 12 · 2020: 5 · 2019: 8 · 2018: 4 · 2017: 8 · 2016: 13 · 2015: 5 · 2014: 13 · 2013: 4 · 2012: 1
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1r03mh082369-01a1)
- National Institute of Mental Health (R03 MH082369, 1R03MH082369)
- National Cancer Institute (R01CA097061, R01CA058316, T32CA009503)
- National Institute of General Medical Sciences (R01GM085081, T32GM008281)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2, MDMX, E3 ubiquitin ligase inhibitors, p53 ubiquitination, small molecule inhibitors, cell death, anticancer agents, high-throughput screening
- MeSH terms
- Cell Survival, DNA Damage, Enzyme Inhibitors, Humans, Nuclear Proteins, Oncogenes, Proto-Oncogene Proteins, Transcription, Genetic, Tumor Suppressor Protein p53, Apoptosis, Cell Cycle Proteins, Ubiquitin-Protein Ligases, HCT116 Cells, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2, Ubiquitination, High-Throughput Screening Assays
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