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J. Biol. Chem., Vol. 279, Issue 15, 14713-14725, April 9, 2004

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Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases^*

Daniel F. McCain, Li Wu, Peter Nickel¶, Matthias U. Kassack¶, Annett Kreimeyer¶, Antonio Gagliardi||**, Delwood C. Collins||, and Zhong-Yin Zhang

From the Departments of Biochemistry and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, the ^¶Pharmaceutical Institute, University of D-53121 Bonn, Germany, and the ^||Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0305

Protein-tyrosine phosphatases (PTPs) are important signaling enzymes that have emerged within the last decade as a new class of drug targets. It has previously been shown that suramin is a potent, reversible, and competitive inhibitor of PTP1B and Yersinia PTP (YopH). We therefore screened 45 suramin analogs against a panel of seven PTPs, including PTP1B, YopH, CD45, Cdc25A, VHR, PTP, and LAR, to identify compounds with improved potency and specificity. Of the 45 compounds, we found 11 to have inhibitory potency comparable or significantly improved relative to suramin. We also found suramin to be a potent inhibitor (IC₅₀ = 1.5 µM) of Cdc25A, a phosphatase that mediates cell cycle progression and a potential target for cancer therapy. In addition we also found three other compounds, NF201, NF336, and NF339, to be potent (IC₅₀ < 5 µM) and specific (at least 20–30-fold specificity with respect to the other human PTPs tested) inhibitors of Cdc25A. Significantly, we found two potent and specific inhibitors, NF250 and NF290, for YopH, the phosphatase that is an essential virulence factor for bubonic plague. Two of the compounds tested, NF504 and NF506, had significantly improved potency as PTP inhibitors for all phosphatases tested except for LAR and PTP. Surprisingly, we found that a significant number of these compounds activated the receptor-like phosphatases, PTP and LAR. In further characterizing this activation phenomenon, we reveal a novel role for the membrane-distal cytoplasmic PTP domain (D2) of PTP: the direct intramolecular regulation of the activity of the membrane-proximal cytoplasmic PTP domain (D1). Binding of certain of these compounds to PTP disrupts D1-D2 basal state contacts and allows new contacts to occur between D1 and D2, which activates D1 by as much as 12–14-fold when these contacts are optimized.

Received for publication, November 14, 2003 , and in revised form, January 6, 2004.

^* This work was supported by National Institutes of Health Grants AI48506 and 1U54 AI057158 and by funds from the G. Harold and Leila Y. Mathers Charitable Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Present address: Sao Paulo Heart Institute, Sao Paulo, Brazil.

An Irma T. Hirschl Career Scientist. To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-4288; Fax: 718-430-8922; E-mail: zyzhang{at}aecom.yu.edu.

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