Awakening guardian angels: drugging the p53 pathway
Abstract
Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein-protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants. Finally, cell-based assays are being used to discover compounds that exploit the p53 pathway by either seeking targets and compounds that show synthetic lethality with TP53 mutations or by looking for non-genotoxic activators of the p53 response.
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Around 22 million cancer patients have defects in p53 signalling.
“Around 22 million cancer patients have defects in p53 signalling77.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [77]
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Self-citationActivation of p53 by MDM2 Antagonists Can Protect Proliferating Cells from Mitotic Inhibitors
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From the Cover: p53 accumulates but is functionally impaired when DNA synthesis is blocked
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“Another consequence of MDM2–MDM4 heterodimerization is that MDM4 can be ubiquitylated by MDM2and is consequently degrade”
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p53 accumulates but is functionally impaired when DNA synthesis is blocked
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“Another consequence of MDM2–MDM4 heterodimerization is that MDM4 can be ubiquitylated by MDM2and is consequently degrade”
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Systematic identification of genomic markers of drug sensitivity in cancer cells
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Translating p53 into the clinic
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Protein Folding and Mechanisms of Proteostasis
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MDM4 is a key therapeutic target in cutaneous melanoma
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Targeting the MDM2–p53 Protein–Protein Interaction for New Cancer Therapy: Progress and Challenges
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Hydrocarbon Stapled Peptides as Modulators of Biological Function
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A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53
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The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway.
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Paradoxical suppression of cellular senescence by p53
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The complexity of TRIM28 contribution to cancer
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A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis.
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Structure of the Stapled p53 Peptide Bound to Mdm2
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MicroRNA regulation of core apoptosis pathways in cancer
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Halogen-Enriched Fragment Libraries as Leads for Drug Rescue of Mutant p53
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- Authors
- Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Medical Research Council (GB)
- Corresponding author
- Lane, David P.
- Venue
- Nature Reviews Cancer
- Published
- 2009-12
- Volume
- 9
- Issue
- 12
- Pages
- 862-873
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2093775600
- Cited by
- 881
- References
- 149
- Citations by year
- 2026: 5 · 2025: 24 · 2024: 21 · 2023: 64 · 2022: 27 · 2021: 32 · 2020: 37 · 2019: 49 · 2018: 42 · 2017: 59 · 2016: 58 · 2015: 76 · 2014: 91 · 2013: 74 · 2012: 82
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- p53 pathway, TP53 mutation, MDM2, p53 activation, mutant p53, synthetic lethality, cell-based assays, anticancer drug development, protein-protein interaction inhibitors
- MeSH terms
- Antineoplastic Agents, Humans, Mutation, Neoplasms, Drug Design, Signal Transduction, Genes, p53, Tumor Suppressor Protein p53, Drug Delivery Systems, Proto-Oncogene Proteins c-mdm2
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