New Approaches to Difficult Drug Targets: The Phosphatase Story.

The drug discovery landscape is littered with promising therapeutic targets that have been abandoned because of insufficient validation, historical screening failures, and inferior chemotypes. Molecular targets once labeled as "undruggable" or "intractable" are now being more carefully interrogated, and while they remain challenging, many target classes are appearing more approachable. Protein tyrosine phosphatases represent an excellent example of a category of molecular targets that have emerged as druggable, with several small molecules and antibodies recently becoming available for further development. In this review, we examine some of the diseases that are associated with protein tyrosine phosphatase dysfunction and use some prototype contemporary strategies to illustrate approaches that are being used to identify small molecules targeting this enzyme class.