Drugging Protein Tyrosine Phosphatases through Targeted Protein Degradation
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Published:2024-01-17
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Volume:
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ISSN:1860-7179
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Container-title:ChemMedChem
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language:en
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Short-container-title:ChemMedChem
Author:
Miao Jinmin1,
Zhang Zhong-Yin2
Affiliation:
1. Purdue University Borch Department of Medicinal Chemistry and Molecular Pharmacology UNITED STATES
2. Purdue University Medicinal Chemistry and Molecular Pharmacology 720 Clinic Drive 47907 West Lafayette UNITED STATES
Abstract
Protein tyrosine phosphatases (PTPs) are an important class of enzymes that regulate protein tyrosine phosphorylation levels of a large variety of proteins in cells. Anomalies in protein tyrosine phosphorylation have been associated with the development of numerous human diseases, leading to a heightened interest in PTPs as promising targets for drug development. However, therapeutic targeting of PTPs has faced skepticism about their druggability. Besides the conventional small molecule inhibitors, proteolysis‐targeting chimera (PROTAC) technology offers an alternative approach to target PTPs. PROTAC molecules utilize the ubiquitin‐proteasome system to degrade specific proteins and have unique advantages compared with inhibitors: 1) PROTACs are highly efficient and can work at much lower concentrations than that expected based on their biophysical binding affinity; 2) PROTACs may achieve higher selectivity for the targeted protein than that dictated by their binding affinity alone; and 3) PROTACs may engage any region of the target protein in addition to the functional site. This review focuses on the latest advancement in the development of targeted PTP degraders and deliberates on the obstacles and prospective paths of harnessing this technology for therapeutic targeting of the PTPs.
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology