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

  • Matthew J. LaMarche*
    Matthew J. LaMarche
    Global Discovery Chemistry, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
    *Email: [email protected]
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Cite this: J. Med. Chem. 2020, 63, 22, 13578–13594
Publication Date (Web):September 10, 2020
https://doi.org/10.1021/acs.jmedchem.0c01170
Copyright © 2020 American Chemical Society

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    Supporting Info (2)»

    Abstract

    Abstract Image

    SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

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    • Selectivity data, histopathology, X-ray data tables, and chemistry experimental details (PDF)

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    PDB codes are 7JVM for SHP2 in complex with compound 1 and 7JVN for SHP2 in complex with compound 24. Authors will release the atomic coordinates data upon article publication.

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