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Updated: Jul 15, 2026

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
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Uncompetitive Allosteric Inhibition of PTP1B by BP-1-102 Reveals a Potential Dual-Target Strategy toward the

Martín González-Andrade1, Rodolfo A Lizárraga-Valadez1, Alejandro Sosa-Peinado2

  • 1Laboratorio de Biosensores y Modelaje Molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, México.

ACS Medicinal Chemistry Letters
|July 14, 2026
PubMed

Insights

A novel dual-target inhibitor, BP-1-102, effectively inhibits both protein tyrosine phosphatase 1B (PTP1B) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. This dual action offers a promising strategy against cancers co-activating these oncogenic pathways.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Selective protein tyrosine phosphatase 1B (PTP1B) inhibitors can paradoxically enhance oncogenic STAT3 signaling by reactivating JAK2.
  • This highlights the need for dual-target strategies to effectively inhibit the PTP1B-JAK2-STAT3 axis in cancer.

Purpose of the Study:

  • To investigate BP-1-102, an orally bioavailable inhibitor, for its dual inhibitory activity against PTP1B and STAT3.
  • To elucidate the mechanism of action and binding mode of BP-1-102.

Main Methods:

  • Enzyme inhibition assays to determine IC50 values and selectivity over TCPTP.
  • Kinetic analysis to identify the inhibition mechanism.
  • Molecular docking and 500 ns molecular dynamics simulations to predict binding mode.
  • Umbrella sampling simulations to assess membrane permeability.

Main Results:

  • BP-1-102 potently inhibits PTP1B (IC50 values of 5.32 μM and 11.7 μM) with significant selectivity over TCPTP (≥37.7-fold).
  • An uncompetitive inhibition mechanism was identified, with binding occurring at a site distal to the active site.
  • Molecular simulations revealed a dual-anchor binding mode involving specific protein regions absent in TCPTP.
  • Favorable passive membrane permeability was confirmed.

Conclusions:

  • BP-1-102 acts as a dual-function inhibitor targeting the PTP1B-JAK2-STAT3 oncogenic axis.
  • Its physicochemical properties and mechanism of action support further evaluation in tumors with coactivated PTP1B and STAT3.
Keywords:
PTP1B inhibitorsallosteric inhibitordual-target cancer therapymolecular dynamicsprotein tyrosine phosphatase 1Bumbrella sampling

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