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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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 [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]
Citations
Cites
p53, the cellular gatekeeper for growth and division
Levine, A. J. (1997) · Cell · doi:10.1016/s0092-8674(00)81871-1 · Cited by 7,693
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
A System for Stable Expression of Short Interfering RNAs in Mammalian Cells
Brummelkamp, T. R., Bernards, R., & Agami, R. (2002) · Science · doi:10.1126/science.1068999 · Cited by 4,295
Live or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,231
p53 is required for radiation-induced apoptosis in mouse thymocytes
Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A., & Jacks, T. (1993) · Nature · doi:10.1038/362847a0 · Cited by 2,864
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206
WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.
El‐Deiry, W. S., Harper, J. W., O'Connor, P. M., Velculescu, V. E., Ce, C., Jackman, J., Pietenpol, J. A., Burrell, M., De, H., & Wang, Y. (1994) · PubMed · Cited by 2,021
Restoration of p53 function leads to tumour regression in vivo
Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T. (2007) · Nature · doi:10.1038/nature05541 · Cited by 1,820
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Research works printed but not linked: 2
- CG Maki, JM Huibregtse, PM Howley Cancer Res 56, 2649–2654 (1996).
- WS el-Deiry, JW Harper, PM O'Connor, VE Velculescu, CE Canman, J Jackman, JA Pietenpol, M Burrell, DE Hill, Y Wang, et al. Cancer Res 54, 1169–1174 (1994).
Cited by
Sorted by citations
Apoptosis in cancer: from pathogenesis to treatment
Wong, R. S. (2011) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-30-87 · Cited by 2,836
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610
Yu, J., Shi, F. J., & Gong, L. (2011) · Accounts of Chemical Research · doi:10.1021/ar2000343 · Cited by 905
Lu, H., Zhou, Q., He, J., Jiang, Z., Peng, C., Tong, R., & Shi, J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00315-3 · Cited by 891
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881
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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