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Dual-specificity phosphatases as targets for antineoplastic agents

Nature Reviews Drug Discovery volume 1, pages 961–976 (2002)Cite this article

Key Points

  • Dual-specificity phosphatases (DSPases) are a sub-class of the more ubiquitous protein tyrosine phosphatases (PTPases) that are uniquely able to hydrolyse the phosphate ester bond on both a tyrosine residue and either a serine or threonine residue located on the same protein.

  • Cell-division cycle 25 (CDC25) DSPases are attractive targets for novel mechanism-based anticancer agents, as they have a crucial role in controlling cell-cycle progression and genetic instability.

  • Small-molecule inhibitors, many based on natural-product scaffolds, are becoming available that allow the reversible and graded regulation of this enzyme family. Such compounds will be valuable tools to probe the function of DSPases. Moreover, they could form the basis for a new class of therapeutic agents.

Abstract

Dual-specificity protein phosphatases are a subclass of protein tyrosine phosphatases that are uniquely able to hydrolyse the phosphate ester bond on both a tyrosine and a threonine or serine residue on the same protein. Dual-specificity phosphatases have a central role in the complex regulation of signalling pathways that are involved in cell stress responses, proliferation and death. Although this enzyme family is increasingly the target of drug discovery efforts in pharmaceutical companies, a summary of the salient developments in the biology and medicinal chemistry of dual-specificity phosphatases has been lacking. We hope that this comprehensive overview will stimulate further progress in the development of small-molecule inhibitors that could form the basis for a new class of target-directed therapeutic agents.

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Figure 1: Mammalian CDC25 phosphatases.
Figure 2: Spatial regulation of CDC25 phosphatases at the G2/M checkpoint.
Figure 3: CDC25 phosphatases promote mammalian cell-cycle progression.
Figure 4
Figure 5: Natural-product analogues.
Figure 6
Figure 7
Figure 8: Synthetic inhibitors.
Figure 9
Figure 10

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Authors and Affiliations

  1. Department of Chemistry, Chevron Science Center, University of Pittsburgh, Pittsburgh, 15260, Pennsylvania, USA

    Michael A. Lyon & Peter Wipf

  2. Department of Pharmacology, Biomedical Science Tower, University of Pittsburgh, Pittsburgh, 15261, Pennsylvania, USA

    Alexander P. Ducruet & John S. Lazo

Authors
  1. Michael A. Lyon
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  2. Alexander P. Ducruet
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  3. Peter Wipf
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  4. John S. Lazo
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Corresponding authors

Correspondence to Peter Wipf or John S. Lazo.

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DATABASES

Cancer.gov

breast cancer

colon cancer

gastric cancer

head-and-neck cancer

non-small-cell lung cancer

non Hodgkin's lymphoma

neuroblastoma

oesophageal squamous-cell carcinoma

LocusLink

ABL

androgen receptor

ASK1

BCR

CDC25A

CDC25B

CDC25C

CDK1

CDK2

CHK1

CHK2

cyclin A

cyclin B

cyclin E

glucocorticoid receptor

GST

oestrogen receptor

p38

progesterone receptor

PTP1B

RAF1

Rb

TP53

VHR

OMIM

Alzheimer's disease

Saccharomyces Genome Database

cdc25

FURTHER INFORMATION

National Cancer Institute

NCI/NIH Developmental Therapeutics Program

Glossary

wee1

A nuclear kinase that inactivates cyclin-dependent kinase 1.

P-LOOP

The phosphate-binding loop formed by the active-site motif of protein tyrosine phosphatases.

UBIQUITYLATION

A multi-step post-translational modification through which ubiquitin, a highly conserved ∼76-amino-acid protein, is covalently linked to a lysine residue in a protein. Ubiquitylation targets proteins for degradation by the proteasome, in what is now called the classic ubiquitin-dependent proteolysis pathway.

CHECKPOINT

A point in the cell cycle at which intracellular conditions are self-inspected and the results determine whether progression through the cell cycle is allowed. There are two main cell-cycle checkpoints: G2/M and G1/S.

G2/M CHECKPOINT

A point in the second gap phase (G2) of the eukaryotic cell cycle at which cell progression into and through mitosis (M phase) is determined.

G1/S ARREST

G1/S arrest occurs at the G1/S checkpoint, at which eukaryotic cells determine if progression from the first gap phase (G1) into and through the DNA synthetic phase (S phase) should occur.

p53

A potent tumour-suppressor protein of 53 kDa that participates in the G1/S checkpoint regulation.

YEAST-TWO-HYBRID SYSTEM

A method to identify the physical interaction between two proteins or peptides within yeast cells by detecting a change in transcriptional activity.

MICHAEL-TYPE NUCLEOPHILIC ADDITION

An addition of a new substituent to a double bond that is conjugated to an electron-accepting functional group.

ARYLATION

The attachment of an aromatic substituent to an organic residue.

FLOW CYTOMETRY

A multi-parametric method in which suspended cells flow through a chamber and can be counted and analysed for size and content of fluorescence-tagged components.

UGI REACTION

The condensation reaction of an amine, an isocyanide, an aldehyde and an acid to form a peptide-like strand.

PICTET–SPENGLER CYCLIZATION

The cyclocondensation of an aromatic ethylamine and an aldehyde or ketone to give a tetrahydroisoquinoline.

REGIOISOMERS

Compounds that differ in the arrangement of substituents.

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Lyon, M., Ducruet, A., Wipf, P. et al. Dual-specificity phosphatases as targets for antineoplastic agents. Nat Rev Drug Discov 1, 961–976 (2002). https://doi.org/10.1038/nrd963

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