CDC25A and B Dual-Specificity Phosphatase Inhibitors: Potential Agents for Cancer Therapy

Antonio      Lavecchia; Carmen      Di Giovanni; Ettore      Novellino

Abstract

Members of the cell division cycle 25 (Cdc25) family of proteins are highly conserved dual specificity phosphatases, which play a fundamental role in transitions between cell cycle phases during normal cell division through the activation of CdK/cyclin complexes. Furthermore, they are important targets of checkpoints in cellular pathways in the response to DNA damage. Over the past few years, more information about the basic enzymology of the Cdc25 phosphatases has emerged, with the identification of three Cdc25 phosphatase isoforms (A, B, and C) in mammalians. In particular, the Cdc25 A and B phosphatases have oncogenic properties and are overexpressed singly in some types of cancers and together in others. Therefore, it is not surprising that the Cdc25s are interesting targets for the development of new anticancer therapeutic strategies. In this review, we examine the most important classes of reversible inhibitors that show specificity for the Cdc25 A and B phosphatases (both singly and together) and the recent advances in the design of new potent Cdc25 A and B inhibitors. Using computational methodologies, we also consider their plausible mechanisms of action.

Keywords: Cancer, dual-specificity phosphatases, Cdc25 inhibitors, cell cycle, antiproliferative agents, docking, molecular modelling