Title

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

Authors

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

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