Awakening guardian angels: drugging the p53 pathway

Key Points

  • p53 functions as the 'guardian of the genome' by inducing cell cycle arrest, senescence and apoptosis in response to oncogene activation, DNA damage and other stress signals. Loss of p53 function occurs in most human tumours by either mutation of TP53 itself or by inactivation of the p53 signal transduction pathway.

  • In many tumours p53 is inactivated by the overexpression of the negative regulators MDM2 and MDM4 or by the loss of activity of the MDM2 inhibitor ARF. The pathway can be reactivated in these tumours by small molecules that inhibit the interaction of MDM2 and/or MDM4 with p53. Such molecules are now in clinical trials.

  • Cell-based screens have been used to find several new non-genotoxic activators of the p53 response, which include inhibitors of protein deacetylating enzymes.

  • Molecules that bind and stabilize mutant p53 — restoring wild-type function — have been discovered by both structure-based design and cell-based screens.

  • Activating a p53-dependent cell cycle arrest in normal cells and tissues can protect them from the toxic effect of anti-mitotic drugs while not reducing their efficacy in killing p53 mutant tumour cells. This drug combination approach represents a new way to exploit the p53 system.

  • The intense study of the p53 pathway is helping to develop new paradigms in drug discovery and development that will have widespread application in other areas of drug discovery.

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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Figure 1: The p53 pathway.
Figure 2: A negative feedback loop controls cellular levels of p53.
Figure 3: Structural applications to p53-based drug therapies.

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Correspondence to David P. Lane.

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DATABASES

National Cancer Institute Drug Dictionary 

actinomycin D

Advexin

BI-2536

chloroquine

doxorubicin

erlotinib

gefitinib

imatinib

lapatinib

ONYX-015

PALA

quinacrine

Pathway Interaction Database 

p53 pathway

FURTHER INFORMATION

Laboratory homepage

Glossary

Cytotoxic chemotherapy

Cell-killing drugs used to treat various cancers by targeting rapidly dividing cells.

Missense mutation

A single nucleotide is changed, resulting in a codon that encodes a different amino acid (non-synonymous).

Forward chemical genetics

FCG. Libraries of small molecules are screened for their ability to induce a particular phenotype in cells or cellular extracts. FCG requires three components: a collection of compounds, a biological assay with a quantifiable phenotypic output and a method to identify the target(s) of the active compounds.

Differential scanning calorimetry

Measures the heat changes that occur in biomolecules during controlled increases or decreases in temperature. It measures the enthalpy of unfolding and the change in heat capacity owing to heat denaturation: the higher the thermal transition (melting point) the more stable the molecule.

Michael acceptor

The Michael reaction occurs between a Michael donor (such as cysteine residues in proteins) and a Michael acceptor molecule (such as leptomycin B) in the presence of a base. The reaction itself is the nucleophillic addition of a carbanion to an α-, β-unsaturated carbonyl compound.

Synthetic lethality

Two genes are in a synthetic lethal relationship if a mutation in both genes leads to cell death but a mutation in one gene alone does not.

Aptamers

Molecules that interact with a specific target molecule usually generated from a large random artificial library, which can be RNA-, DNA-, peptide- or protein-based.

Cis-imidazoline compounds

A class of compounds synthesized around a core imidazole structure, such as the nutlins.

Benzodiazepenes

Chemical compounds with a core chemical structure that is the fusion of a benzene ring and a diazepine ring.

Spiro-oxindole

A molecule with a core scaffold that contains a tryptophan-like structure.

IC50

The concentration of a drug that causes a 50% inhibition of the activity of a target enzyme.

Topoisomerse inhibitors

Chemotherapy agents that interfere with the actions of topoisomerase 1 and topoisomerase 2, which are involved in DNA replication during the cell cycle.

Taxol

A compound that stabilizes microtubules by irreversibly binding to the β-subunit of tubulin.

Vinca alkaloids

Anti-mitotic and anti-microtubule agents that prevent tubulin polymerization and so interfere with chromosomal replication and subsequent separation.

Roscovitine

An olomoucine-related purine flavopiridol, which is a highly potent inhibitor of the kinase activity of cyclin-dependent kinases CDK1, CDK2, CDK5 and CDK7. It induces the activation, stabilization and accumulation of p53 in the nucleus through the suppression of MDM2 expression and partial inhibition of its transcription.

Neutropenia

A haematological disorder characterized by an abnormally low number of neurophils.

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Brown, C., Lain, S., Verma, C. et al. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9, 862–873 (2009). https://doi.org/10.1038/nrc2763

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