Targeting Tyrosine Phosphatases: Time to End the Stigma

Abstract

Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, and several PTPs have been validated as therapeutic targets for human diseases. Historically, development of drugs targeting PTPs has been highly challenging, leading to stigmatization of these enzymes as undruggable targets. Despite these difficulties, efforts to drug PTPs have persisted, and recent years have seen an influx of new probes, providing opportunities for biological examination of old and new PTP targets. Here we will discuss progress towards drugging PTPs, with special emphasis on development of selective probes with biological activity. We will describe development of new small-molecule orthosteric, allosteric and oligomerization PTP inhibitors, and discuss new studies targeting the receptor PTP subfamily with biologics.

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

“…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].…”

X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors

“…34 Indeed, no PTP inhibitors have yet been approved for clinical use despite the clear physiological importance of these enzymes and their complementary activity to the well-established kinase drug targets. 35 …”

New Approaches to Difficult Drug Targets: The Phosphatase Story

“…40 The goal of this review is to focus on recent advances in identifying promising PTP inhibitors, amplifying the comments found in several reviews that previously discussed the challenges of targeting PTPs. 1,31,32,37,40,41 By far the most popular lead compound discovery approach, built on the successful identification of tyrosine kinase inhibitors, has been the use of automated high-throughput in vitro screens with purified recombinant enzyme and artificial substrates that employed either fluorescent or colorimetric end points. Artificial substrates, such as para-nitrophenyl phosphate, 3-O-methylfluorescein phosphate, fluorescein diphosphate, and 6,8-difluoro-4-methylumbelliferyl phosphate, have commonly been used, because they are inexpensive, stable in aqueous solutions, and easy to adapt to automated highthroughput platforms, and they do not require prior knowledge about the protein substrate or its ability to dephosphorylate phosphorylated peptides in vitro.…”