The mode of action of the Protein tyrosine phosphatase 1B inhibitor Ertiprotafib.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of diabetes and obesity. Ertiprotafib is a PTP1B inhibitor that reached the clinical trial stage for the treatment of diabetes. Interestingly, Ertiprotafib reduces the melting temperature of PTP1B in differential scanning fluorimetry (DSF) assays, different from most drugs that increase the stability of their target upon binding. No molecular data on how Ertiprotafib functions has been published. Thus, to gain molecular insights into the mode of action of Ertiprotafib, we used biomolecular NMR spectroscopy to characterize the molecular details of the PTP1B:Ertiprotafib interaction. Our results show that Ertiprotafib induces aggregation of PTP1B in a concentration dependent manner. This shows that the insufficient clinical efficacy and adverse effects caused by Ertiprotafib is due to its tendency to cause aggregation of PTP1B.

• Authors: Ganesan Senthil Kumar, Rebecca Page, Wolfgang Peti
• Journal: PloS one (PLoS One) Vol. 15 Issue 10 Pg. e0240044 ( 2020) ISSN: 1932-6203 [Electronic] United States
• PMID: 33007022 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Phenylpropionates
• Thiophenes
• ertiprotafib
• Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics

• Catalytic Domain
• Enzyme Inhibitors (pharmacology)
• Humans
• Phenylpropionates (pharmacology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (antagonists & inhibitors, chemistry)
• Thiophenes (pharmacology)