Cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell cycle phases during normal cell division, and in the event of DNA damage they are key targets of the checkpoint machinery that ensures genetic stability. Taking only this into consideration, it is not surprising that CDC25 overexpression has been reported in a significant number of human cancers. However, in light of the significant body of evidence detailing the stringent complexity with which CDC25 activities are regulated, the significance of CDC25 overexpression in a subset of cancers and its association with poor prognosis are proving difficult to assess. We will focus on the roles of CDC25 phosphatases in both normal and abnormal cell proliferation, provide a critical assessment of the current data on CDC25 overexpression in cancer, and discuss both current and future therapeutic strategies for targeting CDC25 activity in cancer treatment.

CDC25 phosphatases in cancer cells: key players? Good targets?

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.

Dual-specificity phosphatases as targets for antineoplastic agents

A synthetic vitamin K analogue,
2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone or compound 5 (Cpd
5), was found previously to be a potent inhibitor of tumor cell growth.
We now demonstrate that Cpd 5 arrested cell cycle progression at both
G1 and G2-M. Because of the potential arylating
activity of Cpd 5, it might inhibit Cdc25 phosphatases, which contain a
cysteine in the catalytic site. To test this hypothesis, we examined
the inhibitory activity of Cpd 5 against several cell cycle-relevant
protein tyrosine phosphatases and found that Cpd 5 was a potent,
selective, and partially competitive inhibitor of Cdc25 phosphatases.
Furthermore, Cpd 5 caused time-dependent, irreversible enzyme
inhibition, consistent with arylation of the catalytic cysteine in
Cdc25. Treatment of cells with Cpd 5 blocked dephosphorylation of the
Cdc25C substrate, Cdc2, and its kinase activity. Cpd 5 enhanced
tyrosine phosphorylation of both potent regulators of G1
transition, i.e., Cdk2 and Cdk4, and decreased the
phosphorylation of Rb, an endogenous substrate for Cdk4 kinase.
Furthermore, close chemical analogues that lacked in
vitro Cdc25 inhibitory activity failed to block cell cycle
progression and Cdc2 kinase activity. Cpd 5 did not alter the levels of
p53 or the endogenous cyclin-dependent kinase inhibitors, p21 and p16.
Our results support the hypothesis that the disruption in cell cycle
transition caused by Cpd 5 was attributable to intracellular Cdc25
inhibition. This novel thioalkyl K vitamin analogue could be useful for
cell cycle control studies and may provide a valuable pharmacophore for
the design of future therapeutics.

https://cancerres.aacrjournals.org/content/canres/60/5/1317.full.pdf

Cdc25 inhibition and cell cycle arrest by a synthetic thioalkyl vitamin K analogue.

Caspase-3-mediated Cleavage of the NF-κB Subunit p65 at the NH2 Terminus Potentiates Naphthoquinone Analog-induced Apoptosis

https://www.jbc.org/content/279/15/14713.full.pdf

Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases

Naphthoquinone analogs as inactivators of cdc25 phosphatase

An analysis method of slot-coupled microstripline to waveguide transition is presented to develop a simple but accurate equivalent circuit model. The equivalent circuit consists of an ideal transformer, microstrip open stub, and admittance element looking into a waveguide and a half space of feed side from a slot center. The related circuit element values are calculated by applying the reciprocity theorem, the Fourier transform and series representation, the complex power concept, and the spectral-domain immittance approach. The computed scattering parameters are compared with the measured, and good agreement validates the simplicity and accuracy of the proposed equivalent circuit model.

Equivalent network modeling of slot coupled microstripline to waveguide transition

The paper presents a general theory for the analysis of an aperture-coupled cavity-fed microstrip patch-antenna to develop a simple but accurate equivalent circuit model. The developed equivalent circuit consists of ideal transformers, admittance elements, and transmission lines. These circuit element values are computed by applying the complex power concept, the Fourier transform and series representation, and the spectral-domain immittance approach. The input impedance of the antenna is calculated and compared with the published data. Good agreements validate the simplicity and accuracy of the developed equivalent circuit model.

Won Ho Kim

Papers

Naphthoquinone analogs as inactivators of cdc25 phosphatase

Equivalent network modeling of slot coupled microstripline to waveguide transition

Network analysis of aperture-coupled cavity-fed microstrip patch antenna