Cited by 674Cancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancerHeat shock proteins research

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Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition

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Shangary, Sanjeev, Qin, Dongguang, McEachern, Donna, Liu, Meilan, Miller, Rebecca S., Qiu, Su, Nikolovska-Coleska, Zaneta, Ding, Ke, Wang, Guoping, Chen, Jianyong, Bernard, Denzil, Zhang, Jian, Lu, Yipin, Gu, Qingyang, Shah, Rajal B., Pienta, Kenneth J., Ling, Xiaolan, Kang, Sanmao, Guo, Ming, Sun, Yi, Yang, Dajun, Wang, Shaomeng·2008·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0708917105PMC PMC2268798

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Abstract

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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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: McEachern, Donna
Liu, Meilan
Qiu, Su
Ding, Ke
Chen, Jianyong
Bernard, Denzil
Zhang, Jian
Lu, Yipin
Shah, Rajal B.
Pienta, Kenneth J.
Guo, Ming
Sun, Yi
Yang, Dajun
Wang, Shaomeng
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
DOI: 10.1073/pnas.0708917105
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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Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition

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