Cell Division Cycle 25 (Cdc25) Phosphatase Inhibitors as Antitumor Agents

In search of less toxic and more effective anticancer agents, the cell cycle has become an intense subject of research. Cell cycle deregulation associated with the cancerous state occurs through alterations of proto-oncogenes resulting in cellular transformation and tumorigenesis, and therefore, cell cycle oncoproteins are medicinally targetable with chemicals having useful specificity. For example, identification of Cdk (cyclin-dependent protein kinase) deregulation in many cancer cells stimulated interest in the targeting of these enzymes to inhibit the growth of transformed cells. As a result, several Cdk inhibitors have entered clinical trials. More recently, an understanding of the contribution of dual specificity Cdc25 (cell division cycle 25) phosphatases to cancer cell growth has also emerged during the past decade and makes them attractive drug targets. Cdc25s are key Cdk activating proteins and act by dephosphorylation of conserved Cdk Tyr15 and Thr14 residues. Cdc25A and Cdc25B were also discovered to be proto-oncogenes and their overexpression has been found in many cancer cells. Although the strong genetic link between Cdc25s and the molecular pathology of cancer has been rationalized to develop small-molecule inhibitors, the literature on Cdc25 inhibition is in it's infancy. Fortunately, the structure and catalytic mechanism(s) of Cdc25s have been solved to drive the design and development of specific and potent inhibitors of Cdc25 activity. This review summarizes some of the efforts directed toward the discovery of potent and specific inhibitors of Cdc25s, including several K-vitamin based structures discovered by our group, as well as their likely mechanisms of cell growth inhibition.