Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain

    Authors

    B. D. G. Page; S. Fletcher; P. B. Yue; Z. H. Li; X. L. Zhang; S. Sharmeen; A. Datti; J. L. Wrana; S. Trudel; A. D. Schimmer; J. Turkson;P. T. Gunning

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    Abbreviated Journal Title

    Bioorg. Med. Chem. Lett.

    Keywords

    Stat3; Cancer therapeutics; Jak/Stat pathway; Protein-protein; interaction; Inhibitors of apoptosis; SIGNAL TRANSDUCER; GENE-REGULATION; CANCER-CELLS; ACTIVATOR; INHIBITORS; GROWTH; TRANSCRIPTION-3; DIMERIZATION; PROTEIN; ASSAY; Chemistry, Medicinal; Chemistry, Organic

    Abstract

    Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-phosphopeptide complexes (K(i) = 13 mu M), inhibited Stat3-Stat3 protein interactions (IC(50) = 19 mu M) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC(50) = 10 and 16 mu M, respectively). (C) 2011 Elsevier Ltd. All rights reserved.

    Journal Title

    Bioorganic & Medicinal Chemistry Letters

    Volume

    21

    Issue/Number

    18

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    5605

    Last Page

    5609

    WOS Identifier

    WOS:000294051800098

    ISSN

    0960-894X

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