Related Experiment Video

Updated: Jan 30, 2026

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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6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors

Patrick Sarver, Michael Acker, Jeffrey T Bagdanoff

    Journal of Medicinal Chemistry
    |January 29, 2019
    PubMed

    Insights

    Researchers developed novel pyrimidinone inhibitors for SHP2, a protein linked to cancer and immune modulation. These orally effective compounds show improved potency and pharmacokinetics, expanding options for allosteric SHP2 inhibition.

    Area of Science:

    • Medicinal Chemistry
    • Oncology
    • Immunology

    Background:

    • Protein tyrosine phosphatase SHP2 is implicated in cancer and immune modulation via the PD-L1/PD-1 pathway.
    • Previous work optimized a bicyclic SHP2 inhibitor scaffold.
    • Further chemical diversity is needed for allosteric SHP2 inhibitors.

    Purpose of the Study:

    • To develop novel monocyclic pyrimidinone scaffolds as allosteric SHP2 inhibitors.
    • To identify orally efficacious SHP2 inhibitors with improved properties.
    • To expand the chemical space for allosteric SHP2 inhibition.

    Main Methods:

    • Structure-based design and structure-activity relationship (SAR) analysis.
    • Optimization of a fused, bicyclic screening hit into a monocyclic pyrimidinone.
    • Pharmacokinetic profiling and potency assessment of novel inhibitors.

    Main Results:

    • Identification of SHP394 (1), an orally efficacious allosteric SHP2 inhibitor.
    • SHP394 exhibits high lipophilic efficiency, enhanced potency, and improved pharmacokinetics.
    • Several pyrimidinone analogues demonstrated favorable potency and pharmacokinetic profiles.

    Conclusions:

    • The pyrimidinone scaffold represents a novel and effective template for allosteric SHP2 inhibition.
    • This work expands the range of permissible chemical structures for targeting SHP2.
    • The developed inhibitors offer potential therapeutic strategies for cancer and immune-related diseases.

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