Title

A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes

Authors

Authors

X. L. Zhang; P. B. Yue; S. Fletcher; W. Zhao; P. T. Gunning;J. Turkson

Comments

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Abbreviated Journal Title

Biochem. Pharmacol.

Keywords

Stat3; S3I-201; S3I-201 1066; Small-molecule inhibitor; Antitumor; effects; Antitumor cell effects; HUMAN PANCREATIC-CANCER; POTENT ANTITUMOR-ACTIVITY; DNA-BINDING; ACTIVITY; CONSTITUTIVE ACTIVATION; SIGNAL TRANSDUCER; GROWTH-FACTOR; TRANSCRIPTIONAL ACTIVITY; CELL-TRANSFORMATION; CONFERS RESISTANCE; SRC; ONCOPROTEIN; Pharmacology & Pharmacy

Abstract

The molecular modeling of the phosphotyrosine (pTyr)-SH2 domain interaction in the Stat3 Stat3 dimerization, combined with in silico structural analysis of the Stat3 dimerization disruptor. S3I-201, has furnished a diverse set of analogs We present evidence from in vitro biochemical and biophysical studies that the structural analog, S3I-201 1066 directly interacts with Stat3 or the SH2 domain, with an affinity (K(D)) of 2 74 mu M, and disrupts the binding of Stat3 to the cognate pTyr-peptide, GpYLPQTV-NH(2), with an IC(50) of 23 mu M Moreover, S3I-201 1066 selectively blocks the association of Stat3 with the epidermal growth factor receptor (EGFR), and inhibits Stat3 tyrosine phosphorylation and nuclear translocation in EGF-stimulated mouse fibroblasts. In cancer cells that harbor aberrant Stat3 activity, S3I-201 1066 inhibits constitutive Stat3 DNA-binding and transcriptional activities. By contrast, S3I-201 1066 has no effect on Src activation or the EGFR-mediated activation of the Erk1/2(MAPK) pathway S3I-201 1066 selectively suppresses the viability, survival, and malignant transformation of the human breast and pancreatic cancer lines and the v-Src-transformed mouse fibroblasts harboring persistently active Stat3 Treatment with S3I-201 1066 of malignant cells harboring aberrantly active Stat3 down-regulated the expression of c-Myc, Survivin. the matrix metalloprotemase 9, and VEGF The in vivo administration of S3I-201 1066-induced significant antitumor response in mouse models of human breast cancer, which correlates with the inhibition of constitutively active Stat3 and the suppression of known Stat3-regulated genes Our studies identify a novel small-molecule that binds with a high affinity to Stat3, blocks Stat3 activation and function, and thereby induces antitumor response in human breast tumor xenografts harboring persistently active Stat3. (C) 2010 Elsevier Inc. All rights reserved

Journal Title

Biochemical Pharmacology

Volume

79

Issue/Number

10

Publication Date

1-1-2010

Document Type

Article

Language

English

First Page

1398

Last Page

1409

WOS Identifier

WOS:000275811500003

ISSN

0006-2952

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