Targeting Protein Tyrosine Phosphatase 1B (PTP1B) to Improve Insulin Sensitivity Using Indole-Fused Glycyrrhetinic...

Protein Tyrosine Phosphatase 1B (PTP1B) is a crucial enzyme that significantly modulates insulin and leptin signaling, making it a highly promising target for the treatment of type 2 diabetes (T2D). We previously reported the synthesis and inhibitory activity of FC-114, an indole-fused glycyrrhetinic acid derivative that potently inhibits PTP1B. In this study, we synthesized four FC-114 conjugates with amino acids at the C30 position to enhance their inhibitory activity against PTP1B in vitro. The results indicated that incorporating glycine (compound 5a) and serine (compound 5d) substantially enhanced inhibitory activity against PTP1B, achieving up to 4-fold greater potency, with submicromolar IC₅₀ values of 0.64 and 0.54 μM, respectively. Inhibitory assessments of the short form (hPTP1B_1‑285) and long form (hPTP1B_1‑400) of PTP1B, along with enzymatic kinetics studies, molecular docking, and molecular dynamics analyses, suggested a mechanism consistent with uncompetitive inhibition, potentially involving a binding to the disordered C-terminal domain. Furthermore, both FC-114 conjugates with glycine (5a) and arginine (5b) significantly enhanced the mRNA expression of the GLUT4 receptor in C2C12 myoblast cells. Additionally, these compounds reduced glucose levels during the insulin tolerance test in streptozotocin-induced diabetic mice.