Cited by 170Cancer-related Molecular PathwaysHeat shock proteins researchPI3K/AKT/mTOR signaling in cancer

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Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry?

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Wade, Mark, Wahl, Geoffrey M.·2009·Molecular Cancer Research

DOI 10.1158/1541-7786.mcr-08-0423PMC PMC2629357

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Abstract

Genomic and proteomic profiling of human tumor samples and tumor-derived cell lines are essential for the realization of personalized therapy in oncology. Identification of the changes required for tumor initiation or maintenance will likely provide new targets for small-molecule and biological therapeutics. For example, inactivation of the p53 tumor suppressor pathway occurs in most human cancers. Although this can be due to frank p53 gene mutation, almost half of all cancers retain the wild-type p53 allele, indicating that the pathway is disabled by other means. Alternate mechanisms include deletion or epigenetic inactivation of the p53-positive regulator arf, methylation of the p53 promoter, or elevated expression of the p53 regulators Mdm2 and Mdmx. This review discusses current models of p53 regulation by Mdm2 and Mdmx and presents the rationale for design of future Mdmx-specific therapeutics based on our knowledge of its structure and biological functions.

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“Whether the Mdm2 or Mdmx RING domains have ligand binding pockets or grooves is not clear from published crystal structures (8, 20).”
Background
Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation
Wang, Y. V., Wade, M., Wong, E., Li, Y.-C., Rodewald, L. W., & Wahl, G. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701497104 · Cited by 116
Self-citation
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MDM2 and MDMX can interact differently with ARF and members of the p53 family
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Quantitative Lid Dynamics of MDM2 Reveals Differential Ligand Binding Modes of the p53-Binding Cleft
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A Second p53 Binding Site in the Central Domain of Mdm2 Is Essential for p53 Ubiquitination
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Self-citation
Proteome Changes Induced by Knock-Down of the Deubiquitylating Enzyme HAUSP/USP7
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High-Resolution Array-Based Comparative Genomic Hybridization of Bladder Cancers Identifies Mouse Double Minute 4 ( MDM4 ) as an Amplification Target Exclusive of MDM2 and TP53
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Authors: Wade, M., & Wahl, G. M.
Affiliations: Salk Institute for Biological Studies (US)
ORCID: Wade, Mark
Wahl, Geoffrey M.
Venue: Molecular Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2009-01-01
Volume: 7
Issue: 1
Pages: 1-11
ISSN: 1541-7786 (ISSN-L)
1557-3125
DOI: 10.1158/1541-7786.mcr-08-0423
PMC: PMC2629357
OpenAlex: W2161785833
Cited by: 170
References: 116
Citations by year: 2026: 1 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 10 · 2019: 2 · 2018: 2 · 2017: 7 · 2016: 9 · 2015: 15 · 2014: 14 · 2013: 21 · 2012: 18
FWCI: 2.07
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Molecular Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Cancer Institute (R01CA061449, R01‑CA61449)
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, MDMX, p53 regulation, cancer therapy, small molecule drugs, p53 inactivation, ARF, epigenetic silencing, precision oncology, structure-based drug design
MeSH terms: Animals, Humans, Mice, Transgenic, Mutation, Neoplasms, Nuclear Proteins, Proto-Oncogene Proteins, Transcription, Genetic, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Genes, p53, Tumor Suppressor Protein p53, Cell Cycle Proteins, Dimerization, Mice, Proto-Oncogene Proteins c-mdm2

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Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry?

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