Related Experiment Video

Updated: May 12, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

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JAB-3312, a Potent Allosteric SHP2 Inhibitor That Enhances the Efficacy of RTK/RAS/MAPK and PD-1 Blockade Therapies

Di Kang1, Yanping Wang1, Yiwei Lin2

  • 1Department of Pharmacology, Jacobio Pharmaceuticals Co., Ltd., Beijing, China.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 7, 2025
PubMed
Abstract

Insights

JAB-3312, a SHP2 inhibitor, shows promise in combination cancer therapies. It enhances anti-tumor activity with RTK/RAS/MAPK and PD-1 inhibitors, overcoming resistance and improving outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunotherapy

Background:

  • Aberrant activation of the RTK/RAS/MAPK pathway drives cancer development.
  • Targeted therapies face challenges due to pathway feedback and drug resistance.
  • SHP2 is crucial in RTK/RAS/MAPK signaling and PD-1-mediated immunosuppression.

Purpose of the Study:

  • Evaluate JAB-3312 (Sitneprotafib), a SHP2 inhibitor, in combination cancer therapies.
  • Assess JAB-3312's role in overcoming resistance to RTK/RAS/MAPK pathway inhibitors.
  • Explore JAB-3312's combination with PD-1 blockade for enhanced anti-tumor immunity.

Main Methods:

  • Biochemical and cellular assays to determine JAB-3312 potency.
  • In vitro and in vivo studies using cell lines and xenografts.
  • Combination testing with KRASG12C, MEK, EGFR, and PD-1 inhibitors.

Main Results:

  • JAB-3312 potently inhibits SHP2 activity and downstream signaling (ERK phosphorylation).
  • Combination with JAB-3312 significantly enhanced anti-tumor activity of KRASG12C and MEK inhibitors.
  • JAB-3312 improved efficacy in drug-resistant models and enhanced PD-1 blockade therapy.

Conclusions:

  • JAB-3312 combined with RTK/RAS/MAPK inhibitors shows significant anti-tumor effects.
  • Combining JAB-3312 with PD-1 blockade enhances anti-tumor immune response.
  • JAB-3312-based combination therapies warrant further clinical investigation.

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