Inhibition of PTP1B by Trodusquemine (MSI‐1436) Causes Fat‐specific Weight Loss in Diet‐induced Obese Mice

Abstract

Trodusquemine (MSI-1436) causes rapid and reversible weight loss in genetic models of obesity. To better predict the potential effects of trodusquemine in the clinic, we investigated the effects of trodusquemine treatment in a murine model of diet-induced obesity (DIO). Trodusquemine suppressed appetite, reduced body weight (BW) in a fat-specific manner, and improved plasma insulin and leptin levels in mice. Screening assays revealed that trodusquemine selectively inhibited protein-tyrosine phosphatase 1B (PTP1B), a key enzyme regulating insulin and leptin signaling. Trodusquemine significantly enhanced insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) β and STAT3, direct targets of PTP1B, in HepG2 cells in vitro and/or hypothalamic tissue in vivo. These data establish trodusquemine as an effective central and peripheral PTP1B inhibitor with the potential to elicit noncachectic fat-specific weight loss and improve insulin and leptin levels.

Protein-tyrosine Phosphatase 1B Antagonized Signaling by Insulin-like Growth Factor-1 Receptor and Kinase BRK/PTK6 in Ovarian Cancer Cells*

“…2D), highlighting a potential role of PTP1B in restraining ovarian tumor cell function. Consistent with these findings, we observed the opposite effects of treatment of both HOSE cell lines with a specific, small molecule inhibitor of PTP1B, MSI-1436 (17,18). Cell proliferation, which was monitored by BrdU incorporation (Fig.…”

“…When we overexpressed PTP1B in the cancer cell lines, to the levels detected in normal epithelial cells, it resulted in impaired cell invasion and migration, delayed proliferation, and increased cell death through apoptosis. Conversely, we observed that treatment of the normal ovarian surface epithelial cells with a small molecule inhibitor of PTP1B (17,18) led to enhanced proliferation and motility. These data are consistent with a role for PTP1B in attenuating signals that are important for the tumor phenotype.…”

“…Furthermore, dephosphorylation was not observed with any of the other PTPs (PTPN12, -N14, and -N23) that were tested (data not shown), confirming the specificity of PTP1B in this context. We also tested the effects of a small molecular inhibitor of PTP1B, MSI-1436 (17,18), in CAOV-4 cells to determine whether inhibition of the phosphatase had the opposite effect to that observed in the PTP1B overexpression setting. Tyrosine phosphorylation of IRS1, a known substrate of PTP1B (23), increased dramatically following treatment with 5 M MSI-1436 (Fig.…”

New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells

“…Currently, trodusquemine (Fig. 1), a selective PTP1B inhibitor, has reached phase 1 clinical trials and shows interesting preclinical results as antidiabetic agent and appetite suppressant [33,34].…”

Discovery and study of novel protein tyrosine phosphatase 1B inhibitors

“…Unfortunately, most molecules have proven difficult to develop into drugs due to the large weight (>500Da), high negative charges, low cell permeability and poor bioavailability. Up to now, there are only two small molecules proceeding to clinical research phase, MIS-1436 entering into phase I clinical trials [4] and ISIS113718 entering into phase clinical trials [5]. Therefore, it is still important to develop new drugs targeting PTP1B for the treatment of diabetes and obesity.…”