Small molecule inhibitors of dual specificity protein phosphatases

One hallmark of neoplasia is the deregulation of eel cycle control mechanis ms, which is secondary to altered protein phosphorylation, Dual specificity protein phosphatases uniquely dephosphorylate both phosphoserines/ threoni nes and phosphotyrosines on the same protein substrate. As a class they reg ulate intracellular signaling through the mitogen activated and stress acti vated kinases and govern cellular movement through G1/S and G2/M cell cycle checkpoints by affecting the activity of cyclin-dependent kinases, In part icular, the Cdc25 phosphatases, which dephosphorylate cyclin-dependent kina ses, are overexpressed in many human tumors and this increased expression i s associated with a poor prognosis. In addition to expression levels, the i ntracellular activity of Cdc25 phosphatases is determined by their subcellu lar distribution and physical proximity to substrates. Small molecules that either inhibit the catalytic activity or alter the subcellular distributio n of these dual specificity protein phosphatases could provide effective to ols to interrogate the role of phosphorylation pathways and may afford new approaches to the management of cancer.