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In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Abstract
MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.
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In the citing paper
“WB138 increases the levels of both p53 and MDM2, which is consistent with the activity of previous reports on MDM2 inhibitors[28,32–36].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [32]
In the citing paper
“Nutlin-3a had the strongest activity, and its binding activity with MDM2 reached 90 nM.”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [20]
In the citing paper
“At 200 mg/kg, twice a day, 20 days after oral administration of Nutlin-3a, the tumor growth inhibition rate reached 90%, with no obvious side effects [20].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [20]
In the citing paper
“Moreover, others have shown that inhibition of MDM2 binding to p53 or p73α appears to be more effective at promoting p53- and p73α-mediated apoptosis in cancer cells compared with normal cells.19,45”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [45]
In the citing paper
“Nutlin-3a is a small molecule, which binds to the N-terminal hydrophobic pocket of Mdm2 and blocks protein-protein interactions (PPIs) between Mdm2 and p53 (10).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [10]
In the citing paper
“It has been reported that a consequence of Nutlin treatment is elevated Mdm2 protein levels, and this occurs in cells with or without p53 (6,8).”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [6]
In the citing paper
“Nutlin-3 is a small molecule inhibitor of Mdm2/p53 interaction that can induce apoptosis in cancer cells through activation of p53.”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [6]
In the citing paper
“Nonmalignant tissues tolerate inhibition of Mdm2, and no overt toxicity was observed in preclinical in vivo models.9,11”
From Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death (2013) · cites this paper as [9]
In the citing paper
“For example, small molecule antagonism of the Mdm2–p53 interaction promotes p53-dependent tumor regression in murine models [102,103].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [103]
In the citing paper
“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 [96]
In the citing paper
“To utilize MDM2 for the PROTAC system, the discovery of nutlins, small molecules that bind MDM2 at the p53 interaction interface, was a crucial step [66].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [66]
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Metadata
- Authors
- Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., Fotouhi, N., & Liu, E. A.
- Affiliations
- Department of Discovery Oncology, Roche Research Center, Hoffmann–La Roche, Inc., Nutley, NJ 07110, USA.
- Corresponding author
- Vassilev, Lyubomir T.
- Venue
- Science
- Published
- 2004-02-06
- Volume
- 303
- Issue
- 5659
- Pages
- 844-848
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2097933346
- Cited by
- 4,661
- References
- 21
- Citations by year
- 2026: 119 · 2025: 166 · 2024: 169 · 2023: 203 · 2022: 204 · 2021: 199 · 2020: 226 · 2019: 212 · 2018: 216 · 2017: 209 · 2016: 258 · 2015: 248 · 2014: 296 · 2013: 273 · 2012: 265
- FWCI
- 83.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM2, p53, small molecule antagonists, p53 stabilization, p53-MDM2 interaction, cancer therapy, cell cycle arrest, apoptosis, tumor xenografts, crystal structure
- MeSH terms
- Animals, Binding Sites, Cell Cycle, Cell Division, Cell Line, Cell Survival, Crystallization, Dose-Response Relationship, Drug, Humans, Imidazoles, Mice, Nude, Models, Molecular, Molecular Weight, Neoplasm Transplantation, Neoplasms, Experimental, Nuclear Proteins, Phosphorylation, Piperazines, Protein Conformation, Proto-Oncogene Proteins, Stereoisomerism, Transplantation, Heterologous, Gene Expression, Genes, p53, Tumor Suppressor Protein p53, Cyclins, Apoptosis, Crystallography, X-Ray, NIH 3T3 Cells, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Mice, Proto-Oncogene Proteins c-mdm2, Hydrophobic and Hydrophilic Interactions
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