The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition
Open accessAbstract
We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2–p53 interaction. MI-219 binds to human MDM2 with a K i value of 5 nM and is 10,000-fold selective for MDM2 over MDMX. It disrupts the MDM2–p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.
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“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 [11]
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 [102]
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Flagged first, then by citations
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Metadata
- Authors
- Shangary, S., Qin, D., McEachern, D., Liu, M., Miller, R. S., Qiu, S., Nikolovska-Coleska, Z., Ding, K., Wang, G., Chen, J., Bernard, D., Zhang, J., Lu, Y., Gu, Q., Shah, R. B., Pienta, K. J., Ling, X., Kang, S., Guo, M., Sun, Y., Yang, D., & Wang, S.
- Affiliations
- University of Michigan (US)
- *Comprehensive Cancer Center and Department of Internal Medicine and
- Ascenta Therapeutics, Inc., Malvern, PA 19355
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-03-11
- Volume
- 105
- Issue
- 10
- Pages
- 3933-3938
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2268798
- OpenAlex
- W1992947288
- Cited by
- 660
- References
- 42
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 16 · 2023: 25 · 2022: 23 · 2021: 22 · 2020: 35 · 2019: 34 · 2018: 29 · 2017: 28 · 2016: 42 · 2015: 43 · 2014: 65 · 2013: 45 · 2012: 67
- FWCI
- 30.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Prostate Cancer Foundation (P30CA046592)
- Leukemia and Lymphoma Society
- National Institutes of Health
- National Cancer Institute (R01CA121279, P50CA069568, P30CA046592)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2 inhibitors, p53 activation, p53-MDM2 interaction, selective apoptosis, tumor growth inhibition, tumor xenografts, oral anticancer drugs, cell cycle arrest
- MeSH terms
- Administration, Oral, Animals, Antineoplastic Agents, Cell Cycle, Humans, Indoles, Models, Molecular, Neoplasms, Protein Binding, Spiro Compounds, Time Factors, Tumor Suppressor Protein p53, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2
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