Cited by 914Cancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancerCancer Mechanisms and Therapy

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Awakening guardian angels: drugging the p53 pathway

Brown, Christopher J., Lain, Sonia, Verma, Chandra S., Fersht, Alan R., Lane, David P.·2009·Nature Reviews Cancer

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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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Additional file 2 of Helicobacter pylori-induced NAT10 stabilizes MDM2 mRNA via RNA acetylation to facilitate gastric cancer progression
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Additional file 3 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
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Additional file 1 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
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Additional file 22 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
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Additional file 5 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
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Additional file 23 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
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Additional file 21 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
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Additional file 10 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
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Additional file 26 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040765
Additional file 11 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040702
Additional file 12 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040705
Additional file 19 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040732
Additional file 16 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040723
Additional file 7 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040687
Additional file 13 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040711
Additional file 27 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040768
Additional file 17 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040726
Additional file 1 of A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor
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Additional file 15 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040720
Additional file 28 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040771
Additional file 24 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040759
Additional file 2 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040666
Additional file 8 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040690
Additional file 9 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040696
Additional file 6 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040684
Additional file 18 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040729
Additional file 14 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040717
Additional file 1 of TP53 and TP53-associated genes are correlated with the prognosis of paediatric neuroblastoma
Wang, H., Wang, X., Xu, L., & Zhang, J. (2022) · Figshare · doi:10.6084/m9.figshare.19980627
Additional file 25 of Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
Wong, K., Abascal, F., Ludwig, L., Aupperle‐Lellbach, H., Grassinger, J. M., Wright, C. W., Allison, S. J., Pinder, E., Phillips, R. M., Romero, L. P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24040762
Additional file 1 of Helicobacter pylori-induced NAT10 stabilizes MDM2 mRNA via RNA acetylation to facilitate gastric cancer progression
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BindingDB Entry 50007236: Antitumoral activity of quinoxaline derivatives: A systematic review.
BindingDB (2021) · UC San Diego · doi:10.7270/q2jh3qgv
BindingDB Entry 50007118: α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53-MDM2/MDMX Protein-Protein Interactions.
BindingDB (2021) · UC San Diego · doi:10.7270/q2d79fph
BindingDB Entry 50043777: TBA
BindingDB (2014) · UC San Diego · doi:10.7270/q20v8f7s
BindingDB Entry 50045594: Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment.
BindingDB (2016) · UC San Diego · doi:10.7270/q21g0nz5
BindingDB Entry 50004792: Small molecules that target protein misfolding.
BindingDB (2020) · UC San Diego · doi:10.7270/q2qj7m50
BindingDB Entry 50014764: Discovery of
BindingDB (2023) · UC San Diego · doi:10.7270/q2z03d1v
BindingDB Entry 50001621: Simultaneous Targeting of RGD-Integrins and Dual Murine Double Minute Proteins in Glioblastoma Multiforme.
BindingDB (2020) · UC San Diego · doi:10.7270/q22j6fcb
BindingDB Entry 50016713: Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability.
BindingDB (2023) · UC San Diego · doi:10.7270/q2862mgn
BindingDB Entry 50012148: Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein-Protein Interactions.
BindingDB (2022) · UC San Diego · doi:10.7270/q24m986g
BindingDB Entry 50049115: Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction.
BindingDB (2019) · UC San Diego · doi:10.7270/q2jq1381
BindingDB Entry 50044097: Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction.
BindingDB (2015) · UC San Diego · doi:10.7270/q2xd136f
BindingDB Entry 50040300: An ultrahigh affinity d-peptide antagonist Of MDM2.
BindingDB (2013) · UC San Diego · doi:10.7270/q20p1143
BindingDB Entry 50044472: Discovery of 1-arylpyrrolidone derivatives as potent p53-MDM2 inhibitors based on molecule fusing strategy.
BindingDB (2015) · UC San Diego · doi:10.7270/q2qv3p22

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.
ORCID: Brown, Christopher J.
Verma, Chandra S.
Lane, David P.
Venue: Nature Reviews Cancer
Publisher: Springer Science and Business Media LLC
Published: 2009-12
Volume: 9
Issue: 12
Pages: 862-873
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc2763
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › 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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Awakening guardian angels: drugging the p53 pathway

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