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.
Highlights
Protein tyrosine phosphorylation is a key post-translational modification that plays essential roles in cell growth, cell differentiation, cell-cycle regulation and the immune response [1, 2]
Ertiprotafib is a non-competitive inhibitor of Protein tyrosine phosphatase 1B (PTP1B)
Ertiprotafib was initially identified as a potent inhibitor of PTP1B (435 residues; ~50 kDa; the C-terminal ~30 aa form an ER targeting α-helix)
Summary
Protein tyrosine phosphorylation is a key post-translational modification that plays essential roles in cell growth, cell differentiation, cell-cycle regulation and the immune response [1, 2]. Aberrant protein tyrosine phosphorylation due to imbalances in the activities of PTKs and PTPs has been implicated in numerous human diseases including cancer and diabetes [3, 4]. Targeting the activities of PTKs and PTPs have emerged as a promising avenue for the development of drugs to cure cancer and diabetes [5,6,7,8,9]. Protein tyrosine phosphatase 1B, the founding member of the PTP superfamily, is critical for the regulation of insulin signaling as it dephosphorylates both the insulin receptor (IR) and the insulin receptor substrate (IRS) [10,11,12]. While its core catalytic functions are driven by rigid conformational changes, allostery in PTP1B is controlled by conformational and dynamic changes, especially in a PTP1B specific secondary structure element, helix α7 [16]
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