Title

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

Authors

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

Comments

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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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