Targeting Tyrosine Phosphatases: Time to End the Stigma. (June 2017)

• Record Type: Journal Article
• Authors: Stanford, Stephanie M.; Bottini, Nunzio
• Is Part Of: Trends in pharmacological sciences. Volume 38:Number 6(2017)
• Page Start: 524
• Page End: 540
• Publication Date: 2017-06
• Subjects: protein tyrosine phosphatase -- drug target -- inhibitor -- small molecule -- allosteric -- biologic; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2017.03.004
• Languages: English
• ISSNs: 0165-6147

Abstract

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, the 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 discuss progress towards drugging PTPs with special emphasis on the development of selective probes with biological activity. We describe the development of new small-molecule orthosteric, allosteric, and oligomerization-inhibiting PTP inhibitors and discuss new studies targeting the receptor PTP (RPTP) subfamily with biologics. Trends: Protein tyrosine phosphatases (PTPs) are critical for numerous cellular processes in health and disease, and several PTPs are validated drug targets. Despite historical difficulties in drugging PTPs, efforts have persisted and led to the development of new probes that are being used for biological examination of old and new PTP targets. Allosteric PTP inhibitors are emerging, most of which exploit catalytically unfavorable conformations of the targeted enzyme. New studies of receptor PTPs reveal the unique potential in targeting this PTP subfamily with decoy biologics. Small-molecule inhibitors of vascular endothelial PTP and PTP1B are currently undergoing clinical trials for diabetic macular edema and metastatic breast cancer, respectively.