Antagonism of the Stat3-Stat3 Protein Dimer with Salicylic Acid Based Small Molecules

    Authors

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

    Comments

    Authors: contact us about adding a copy of your work at STARS@ucf.edu

    Abbreviated Journal Title

    ChemMedChem

    Keywords

    antitumor agents; molecular recognition; molecular therapeutics; protein-protein interactions; stat3; SOLID-PHASE SYNTHESIS; BREAST-CANCER CELLS; SIGNAL TRANSDUCER; STAT3; ACTIVATION; FLUORESCENCE POLARIZATION; ANTITUMOR-ACTIVITY; PROSTATE-CANCER; IN-VITRO; INHIBITORS; DIMERIZATION; Chemistry, Medicinal; Pharmacology & Pharmacy

    Abstract

    More than 50 new inhibitors of the oncogenic Stat3 protein were identified through a structure-activity relationship (SAR) study based on the previously identified inhibitor S3I-201 (IC(50) = 86 mu M, K(i) > 300 mu M). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the Stat3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting Stat3 DNA binding activity, with an in vitro IC(50) range of 18.7-51.9 mu M, and disruption of Stat3-pTyr peptide interactions with K(i) values in the 15.5-41 mu M range. One agent in particular exhibited potent inhibition of Stat3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of Stat3 target genes, and induced antitumor effects in tumor cells harboring activated Stat3 protein.

    Journal Title

    Chemmedchem

    Volume

    6

    Issue/Number

    8

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    1459

    Last Page

    1470

    WOS Identifier

    WOS:000294112900014

    ISSN

    1860-7179

    Share

    COinS