Selectivity, cell permeability and oral availability studies of novel bromophenol derivative HPN as protein tyrosine phosphatase 1B inhibitor

• Published in: British journal of pharmacology Vol. 175; no. 1; pp. 140 - 153
• Main Authors: Luo, Jiao, Xu, Qi, Jiang, Bo, Zhang, Renshuai, Jia, Xiaoling, Li, Xiangqian, Wang, Lijun, Guo, Chuanlong, Wu, Ning, Shi, Dayong
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2018; John Wiley and Sons Inc
• Subjects: Administration, Oral; Animals; Benzyl Compounds - administration & dosage; Benzyl Compounds - chemistry; Benzyl Compounds - metabolism; Beta cells; Catechols - administration & dosage; Catechols - chemistry; Catechols - metabolism; Cell Membrane Permeability - drug effects; Cell Membrane Permeability - physiology; Cell permeability; Dephosphorylation; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Dose-Response Relationship, Drug; Dyslipidemia; Female; Glycogen; Humans; Hydrogen bonding; Hyperglycemia; Insulin; Liver; Long-term effects; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Muscles; Myocytes; Myotubes; Oral administration; Palmitic acid; Pancreas; Permeability; Phosphatase; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Protein-tyrosine-phosphatase; Random Allocation; Research Paper; Research Papers; Rodents; Signal transduction; Skeletal muscle; Studies; Surface plasmon resonance
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14080

Background and Purpose Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling by tyrosine dephosphorylation of the insulin receptor. It is a highly validated target for type 2 diabetes therapeutics. Here, the anti‐diabetic effects of HPN were evaluated in the diabetic BKS db mice. Experimental Approach The mode of inhibition of PTP1B by HPN was determined according to the Lineweaver–Burk plot. A surface plasmon resonance assay and molecular docking were used to study the interaction between HPN and PTP1B. C2C12 skeletal muscle cells were used to investigate the cell permeability of HPN and the effect of HPN on insulin signalling pathways. Long‐term effects of HPN on glycaemic control were investigated in diabetic BKS db mice. Glycogen contents in liver and muscle were determined. Furthermore, changes in the number of beta cells were evaluated by Gomori staining. Key Results HPN was identified as a specific PTP1B inhibitor. HPN directly interacted with PTP1B by binding to the catalytic domain through hydrogen bonds in a competitive mode. Approximately 56.98% of HPN entered into the cultured C2C12 myotubes. HPN ameliorated the impaired insulin signalling in palmitate‐treated C2C12 myocytes. Notably, oral administration of HPN significantly protected mice from hyperglycaemia, dyslipidemia and hyperinsulinaemia. HPN also enhanced the storage of glycogen in liver and muscle. Moreover, HPN obviously improved the beta cell numbers of the pancreatic islets. Conclusion and Implications Our results indicate that HPN is a specific PTP1B inhibitor, with anti‐diabetic properties and good cell permeability and oral availability.