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Updated: Dec 9, 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

6.5K

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer

Matthew J LaMarche, Michael Acker, Andreea Argintaru

    Journal of Medicinal Chemistry
    |September 10, 2020
    PubMed

    Insights

    Researchers developed TNO155, a novel pyrazine-based inhibitor targeting SHP2 (a protein tyrosine phosphatase involved in cell signaling and cancer). This first-in-class drug shows potent antitumor activity and is orally effective, offering new cancer treatment possibilities.

    Area of Science:

    • Biochemistry
    • Pharmacology
    • Oncology

    Background:

    • SHP2 (PTPN11) is a nonreceptor protein tyrosine phosphatase crucial for cell growth, differentiation, and programmed cell death (PD-1/PD-L1 pathway).
    • SHP2 acts as an oncoprotein and immunomodulator, making its inhibition a significant therapeutic target in cancer treatment.

    Purpose of the Study:

    • To identify and optimize novel allosteric inhibitors of SHP2.
    • To discover a first-in-class, orally efficacious SHP2 inhibitor for cancer therapy.

    Main Methods:

    • Utilized structure and property-based drug design to explore allosteric binding modes of SHP2 inhibition.
    • Optimized chemical scaffolds, focusing on the pyrazine class of inhibitors.
    • Evaluated protein-ligand interactions, cellular inhibition, physicochemical properties, and in vivo antitumor activity.

    Main Results:

    • Identified multiple allosteric binding modes for SHP2 inhibition.
    • Optimized the pyrazine scaffold, leading to the discovery of TNO155.
    • TNO155 demonstrated potent and selective SHP2 inhibition, favorable drug properties, and significant in vivo antitumor efficacy.

    Conclusions:

    • TNO155 is a highly potent, selective, and orally efficacious first-in-class SHP2 inhibitor.
    • The discovery of TNO155 represents a significant advancement in targeting SHP2 for cancer treatment.
    • TNO155 is currently undergoing clinical trials for various cancers.

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