A novel protein tyrosine phosphatase 1B inhibitor with therapeutic potential for insulin resistance.

Background and Purpose Insulin-sensitizing drugs are currently limited, and identifying new candidates is a challenge. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling, and its inhibition is anticipated to improve insulin resistance. Here, the pharmacological properties of CX08005, a novel PTP1B inhibitor, were investigated. Experimental Approach Recombinant hPTP1B protein was used to study enzyme activity and mode of inhibition. Docking simulation explored the interactions between CX08005 and PTP1B. Insulin sensitivity was evaluated by glucose tolerance test (GTT) in diet-induced obese (DIO) and KKAy mice; glucose-stimulated insulin secretion (GSIS), homeostasis model assessment of insulin resistance index (HOMA-IR) and whole-body insulin sensitivity (ISWB) were also determined. A hyperinsulinaemic–euglycaemic clamp was performed to evaluate insulin-stimulated glucose disposal in both whole-body and insulin-sensitive tissues. Furthermore, CX08005's effects on muscle, fat and liver cells were determined in vitro. Key Results CX08005 competitively inhibited PTP1B by binding to the catalytic P-loop through hydrogen bonds. In DIO mice, CX08005 ameliorated glucose intolerance dose-dependently (50–200 mg·kg−1·day−1) and decreased the HOMA-IR. In KKAy mice, CX08005 (50 mg·kg−1·day−1) improved glucose intolerance, GSIS, ISWB and hyperglycaemia. CX08005 also enhanced insulin-stimulated glucose disposal, increased glucose infusion rate and glucose uptake in muscle and fat in DIO mice (hyperinsulinaemic–euglycaemic clamp test). CX08005 enhanced insulin-induced glucose uptake in 3T3-L1 adipocytes and C2C12 myotubes, and increased phosphorylation of IRβ/IRS1 and downstream molecules in hepatocytes in a dose- and insulin-dependent manner respectively. Conclusions and Implications Our results strongly suggest that CX08005 directly enhances insulin action in vitro and in vivo through competitive inhibition of PTP1B.