Uncompetitive Allosteric Inhibition of PTP1B by BP-1-102 Reveals a Potential Dual-Target Strategy toward the PTP1B–STAT3 Oncogenic Axis: Biochemical and Computational Evidence

High Resolution Image Download MS PowerPoint Slide Selective PTP1B inhibitors paradoxically potentiate oncogenic STAT3 signaling by restoring JAK2 activity, underscoring the need for dual-target strategies. Here we report that BP-1-102, an orally bioavailable STAT3 SH2 domain inhibitor, also potently inhibits PTP1B with IC 50 values of 5.32 μM (hPTP1B 1–400 ) and 11.7 μM (hPTP1B 1–285 ), with ≥37.7-fold selectivity over TCPTP. Kinetic analysis identified an uncompetitive mechanism, suggesting inhibitor binding to the enzyme–substrate complex at a site distal to the active site. Docking and 500 ns molecular dynamics simulations revealed a dual-anchor binding mode involving the 113–123 loop (Cys121) and the proline-rich C-terminal disordered region, a structural interface absent in TCPTP. Umbrella sampling confirmed favorable passive membrane permeability through a tumor-mimetic bilayer (Δ G = −13.83 kcal/mol). These results propose BP-1-102 as a candidate for dual-function inhibitor of the PTP1B–JAK2–STAT3 oncogenic axis, providing a physicochemical and mechanistic rationale for its further evaluation in tumors where both targets are coactivated.