New Approaches to Difficult Drug Targets: The Phosphatase Story

Abstract

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.

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

“…In contrast, protein phosphatases have been neglected as potential drug targets because they were classified as 'undruggable', evoking the misconception that it is impossible to target a particular protein phosphatase [4,5,8]. In fact, multiple studies by various research groups revealed that protein phosphatases are unequivocally 'druggable' targets [5,9]. Various small-molecule effectors that modulate (activate or inhibit) protein phosphatase activity and exhibit therapeutic potential for various human diseases have been generated [5,9].…”

“…In fact, multiple studies by various research groups revealed that protein phosphatases are unequivocally 'druggable' targets [5,9]. Various small-molecule effectors that modulate (activate or inhibit) protein phosphatase activity and exhibit therapeutic potential for various human diseases have been generated [5,9]. For example, the immunosuppressants cyclosporine A and FK506, which are successfully used to treat acute organ transplant rejection, rheumatoid arthritis, psoriasis and Crohn's disease, target and inhibit protein serine/threonine phosphatase PP2B, also known as PP3 or calcineurin [4,10,11].…”

“…These PP2B inhibitors do not block the active site but bind and block one of the substrate binding sites of PP2B [12,13]. Various protein tyrosine phosphatase (PTP) inhibitors, including distinct small molecule inhibitors such as orthosteric (binds at the enzyme active site), allosteric (binds outside the enzyme active site) and competitive (binds to an enzyme at the site of substrate binding) inhibitors and biologics [8,9,14] have also been developed for therapeutic purposes. A few are currently undergoing clinical trials.…”

“…A few are currently undergoing clinical trials. For example, small-molecule inhibitors of vascular endothelial PTP and PTP1B are being tested for treatment of diabetic macular edema and metastatic breast cancer, respectively [8,9,14].…”

PP2A: A Promising Biomarker and Therapeutic Target in Endometrial Cancer

“…In the last few years, the notion that phosphatases as opposed to kinases could also be useful therapeutic targets has gained more and more attention (54, 131–134). In contrast to therapeutic inhibition of kinases, the focus with targeting phosphatases, and in particular the tumor suppressive phosphatase PP2A, is on the development of activating or reactivating compounds (133).…”