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Protein tyrosine phosphatase 1B in metabolic diseases and drug development

Nature Reviews Endocrinology (2024)Cite this article

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Abstract

Protein tyrosine phosphatase 1B (PTP1B), a non-transmembrane phosphatase, has a major role in a variety of signalling pathways, including direct negative regulation of classic insulin and leptin signalling pathways, and is implicated in the pathogenesis of several cardiometabolic diseases and cancers. As such, PTP1B has been a therapeutic target for over two decades, with PTP1B inhibitors identified either from natural sources or developed throughout the years. Some of these inhibitors have reached phase I and/or II clinical trials in humans for the treatment of type 2 diabetes mellitus, obesity and/or metastatic breast cancer. In this Review, we summarize the cellular processes and regulation of PTP1B, discuss evidence from in vivo preclinical and human studies of the association between PTP1B and different disorders, and discuss outcomes of clinical trials. We outline challenges associated with the targeting of this phosphatase (which was, until the past few years, viewed as difficult to target), the current state of the field of PTP1B inhibitors (and dual phosphatase inhibitors) and future directions for manipulating the activity of this key metabolic enzyme.

Key points

  • Protein tyrosine phosphatase 1B (PTP1B) has a key role in the pathogenesis and development of a variety of diseases.

  • Cellular signalling of PTP1B and its implications have been studied extensively; PTP1B has a major role in the regulation of energy expenditure, insulin and leptin signalling, glucose and lipid homeostasis, immune responses, and cancer.

  • Numerous PTP1B inhibitors have been identified from natural sources or designed and synthesized in the past few decades, several of which have reached clinical trials in humans.

  • The main challenges associated with the drug discovery process and development of effective therapeutic agents against PTP1B activity have been specificity, selectivity and bioavailability.

  • Selective and potent therapeutic inhibitors of PTP1B have been reported and could offer a promising potential treatment option for several diseases, such as type 2 diabetes mellitus, obesity, cancer and Rett syndrome.

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Fig. 1: The role of PTP1B in different disease states and metabolic conditions.
Fig. 2: An illustration of the effects of PTP1B on insulin and leptin signalling pathways.
Fig. 3: Chemical structures of small-molecule and allosteric inhibitor examples.
Fig. 4: Chemical structures of peptide-based inhibitors.
Fig. 5: Mechanism of action of PROTACs.

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  1. Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK

    Mirela Delibegović, Sergio Dall’Angelo & Ruta Dekeryte

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Delibegović, M., Dall’Angelo, S. & Dekeryte, R. Protein tyrosine phosphatase 1B in metabolic diseases and drug development. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00965-1

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