Protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator for insulin signaling and an effective therapeutic target for T2DM. Ace Therapeutics is committed to utilizing our expertise in diabetes to help clients accelerate the development of effective PTP1B inhibitors. Our reliable diabetes models and comprehensive preclinical services help clients accelerate the development and optimization of effective PTP1B inhibitors.

Overview of PTP1B and PTP1B Inhibitors

Protein tyrosine phosphatase 1B (PTP1B) is one of the major negative regulators of the insulin receptor (IR) signaling pathway and is widely expressed in a variety of cells and tissues. PTP1B contributes to insulin resistance in various tissues by decreasing IR phosphorylation. Experimental results in systemic and tissue-specific PTP1B knockout mice suggest that PTP1B plays a key role in the regulation of metabolic pathways, and its knockout improves obesity, insulin resistance, and glucose tolerance.

Fig. 1 Mechanism of action of PTP1B in insulin and leptin signaling pathways. (Singh, S.; et al., 2022)

PTP1B inhibitors show potential for the treatment of insulin resistance-related diseases, such as type II diabetes and obesity, by increasing insulin receptor sensitivity. In recent years, there has been a growing interest in the development of potent and selective PTP1B inhibitors. These inhibitors have become important targets for the treatment of type II diabetes and obesity by delaying insulin receptor desensitization and prolonging insulin action. Therefore, the latest design and discovery of PTP1B inhibitors have become a hot topic of current research aimed at providing more effective therapeutic options for these diseases.

Antidiabetic Drug Development Services Targeting PTP1B at Ace Therapeutics

As a preclinical CRO specializing in diabetes, we provide comprehensive services from target validation to preclinical development of drug candidates. With the biological mechanism of the PTP1B target and the latest technological breakthroughs, we help our clients to efficiently advance the development of antidiabetic drugs targeting PTP1B.

PTP1B target biology validation service

• Primary hepatocyte/myocyte insulin resistance model to validate PTP1B inhibitory effects.
• High insulin-normal glucose clamp technique to quantitatively assess insulin sensitivity improvement.
• Dual fluorescent reporter system to detect IRS-1/PI3K/Akt pathway activation efficiency.

Preclinical efficacy and safety evaluation services

• In vitro model validation

Cellular level: we assay glucose consumption in insulin-resistant HepG2 cells.

Enzyme kinetic analysis: we validate the inhibitor binding mode by surface plasmon resonance (SPR) and molecular interactions techniques.

Molecular pathway analysis: we detected downstream PI3K/Akt signaling activation, endoplasmic reticulum stress (IRE-1/TRAF2/JNK pathway) and GLUT4 translocation efficiency by Western blot and PCR.

• In vivo model validation

Animal models of diabetes: we used db/db mice (spontaneous T2DM) and STZ-induced models to assess the regulatory effects of PTP1B inhibitors on glycolipid metabolism.

• Safety evaluation services

Toxicity screening: We screen low toxicity candidate compounds by AMES test and liver microsomal stability test.

Tissue specificity evaluation: We verify the selectivity of the inhibitors to homologous proteins such as TCPTP to avoid off-target effects.

Advantages of Our Antidiabetic Drug Development Services Targeting PTP1B

• We conduct enzyme kinetic assays and measure the expression of key insulin signaling pathway proteins (IRS-1, GLUT-1, PI3K/Akt) using IHC/WB analysis.
• We dynamically monitor blood glucose and body weight using customized diabetic animal models to comprehensively evaluate drug efficacy.
• We integrate virtual screening, pharmacophore modeling, and ADMET prediction to help clients identify low-toxicity, high-activity candidate molecules.

Ace Therapeutics is committed to utilizing our preclinical capabilities to provide comprehensive services to our clients. Please contact us for more details and we will be happy to assist you.

References

1. Singh, S.; et al. Recent updates on development of protein-tyrosine phosphatase 1B inhibitors for treatment of diabetes, obesity and related disorders. Bioorganic Chemistry. 121 (2022): 105626.
2. Behl, T.; et al. Exploring protein tyrosine phosphatases (PTP) and PTP-1B inhibitors in management of diabetes mellitus. Biomedicine & Pharmacotherapy. 153 (2022): 113405.

• DGAT-Targeted Drug Development for Diabetes
• KKS-Targeted Drug Development for Diabetes
• FBPase-Targeted Drug Development for Diabetes
• MetAP2-Targeted Drug Development for Diabetes
• ANGPTL3-Targeted Drug Development for Diabetes
• GK-Targeted Drug Development for Diabetes
• AMPK-Targeted Drug Development for Diabetes
• 11β-HSD1-Targeted Drug Development for Diabetes
• GSK-3-Targeted Drug Development for Diabetes
• SGLT2-Targeted Drug Development for Diabetes
• Visfatin-Targeted Drug Development for Diabetes
• PEDF-Targeted Antidiabetic Drug Development Services
• FETUIN-A-Targeted Antidiabetic Drug Development Services
• ACRP30-Targeted Antidiabetic Drug Development Services

• Mouse Models
• Assay Kits
• Antibodies
• Cell Lines & Lysates
• Proteins & Peptides
• Inhibitors & Activators