Protein tyrosine phosphatase non-receptor type 1

Overview

Protein tyrosine phosphatase non-receptor type 1 (PTPN1), commonly known as protein tyrosine phosphatase 1B (PTP1B), is a non-receptor protein tyrosine phosphatase that functions as a key negative regulator of signaling pathways mediated by receptor tyrosine kinases. In the contexts provided, it is described as a major modulator of insulin and leptin signaling, and therefore as an important molecular target in type 2 diabetes, obesity, and broader metabolic dysfunction. By attenuating these pathways, PTP1B can contribute to insulin resistance and impaired metabolic homeostasis.

Recent research also highlights a more complex role for PTP1B in immune and inflammatory biology. In myeloid cells, it has been linked to monocyte and macrophage activation, with implications for diabetic retinopathy and retinal neurodegeneration. This broader biology has made PTP1B a continuing focus of drug discovery efforts, especially for selective inhibitors that could improve glucose homeostasis and metabolic signaling without unacceptable off-target effects.

Recent Publications Focus

Below is a summary of the newest research publications targeting Protein tyrosine phosphatase non-receptor type 1 (sorted by publication date).

Myeloid cell PTP1B and retinal neurodegeneration in diabetic mice (PMID: 42166617)
This study examined the role of myeloid cell PTP1B in retinal damage in diabetic mice, with a focus on diabetic retinopathy and neurodegeneration. The publication context indicates that PTP1B has a complex role in monocyte and macrophage activation, suggesting that myeloid PTP1B may contribute to inflammatory or immune-mediated mechanisms that worsen retinal injury in diabetes. The work used an aged mouse context and a LysMcre-PTP1B fl/fl model, consistent with a cell-type-specific approach to interrogating PTP1B function in myeloid cells.
Structure-based de novo design of dual DPP IV and PTP1B inhibitors (PMID: 42378400)
This medicinal chemistry study pursued dual inhibition of Dipeptidyl peptidase 4 (DPP-IV) and PTP1B as a strategy to improve glucose homeostasis in type 2 diabetes. The publication context states that inhibiting both targets is considered a viable therapeutic approach for managing T2DM. The work involved structure-based de novo design and C5/C7-disubstituted designs, along with computational and drug-likeness evaluation methods including molecular dynamics simulation, MM-GBSA, density functional theory (DFT) calculations, and ADMET assessment. A DPP-IV degradation assay was also used, supporting the dual-target concept.
Discovery of potent and selective PTPN2/N1 dual inhibitors (PMID: 42054654)
Although this paper focused on PTPN2/N1 dual inhibition, it is relevant to the broader PTP1B/PTPN1 target family because PTPN1 and PTPN2 were described as important immuno-oncology targets that modulate IFNγ signaling and T-cell activity. The study used benzothiophene difluoromethyl phosphonate (DFMP) chemistry and reported the discovery of potent and selective dual inhibitors. While not a PTP1B-specific paper, it reflects the therapeutic interest in closely related protein tyrosine phosphatases as immune modulators.
Stapled lipopeptide analogues of BimBH3 as PTP1B inhibitors for diabetes therapy (PMID: 41831409)
This study developed proteolytically stable stapled lipopeptide analogues of BimBH3 as inhibitors of PTP1B for potential diabetes treatment. The publication context emphasizes that PTP1B is a key negative regulator of both insulin and leptin signaling, and that its inhibition may offer a dual-mechanism strategy for type 2 diabetes and obesity by improving insulin sensitivity and leptin signaling simultaneously. The work therefore aligns PTP1B inhibition with metabolic disease intervention rather than with direct hormone replacement or Insulin Therapy.
Flavonoids from Elsholtzia ciliata and metabolic signaling via PTP1B inhibition (PMID: 42113121)
This publication investigated flavonoids (EC2-EC5) isolated from Elsholtzia ciliata and their ability to restore redox electron flow and metabolic signaling in C2C12 skeletal muscle myotubes and Hepa1c1c7 hepatocytes through PTP1B inhibition. The study context describes PTP1B as a key negative regulator of insulin and leptin signaling and notes the lack of clinically approved inhibitors because of selectivity and bioavailability issues. The reported findings support the idea that natural products can modulate PTP1B-linked metabolic pathways in muscle and liver cells.
Cannabisin A and B from hemp seed hulls improve glucose homeostasis via selective PTP1B inhibition (PMID: 41831381)
This study examined Cannabisin A and Cannabisin B from hemp seed hulls as selective PTP1B inhibitors that improve glucose homeostasis by re-engaging insulin, leptin, and AMPK pathways. The publication context describes PTP1B as a master negative regulator of insulin and leptin receptor tyrosine kinase signaling and notes that chronic overactivation is strongly implicated in metabolic dysfunction. The work used oral glucose tolerance tests, and the mechanistic framing connects PTP1B inhibition to improved metabolic signaling rather than to direct agonism of PRKAA1 or other downstream nodes.
Additional related experimental and translational context
Across these publications, PTP1B-targeted research was supported by a range of experimental systems and technologies, including Aged Mice, MC38 mouse model, streptozotocin (STZ), trodusquemine, in vitro plasma stability, and computational chemistry workflows. These methods reflect two major directions in the field: first, mechanistic studies in animal and cell models of diabetes and inflammation; second, discovery-oriented medicinal chemistry aimed at improving potency, selectivity, and pharmacokinetic properties of PTP1B inhibitors.

Target PMIDs

[PMID 42166617]
[PMID 42378400]
[PMID 42054654]
[PMID 41831409]
[PMID 42113121]
[PMID 41831381]