title: Suramin derivatives as inhibitors and activators of protein-tyrosine phosphatases.
abstract: 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, PTPalpha, 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 (IC(50) = 1.5 microm) 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 (IC(50) < 5 microm) 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 PTPalpha. Surprisingly, we found that a significant number of these compounds activated the receptor-like phosphatases, PTPalpha and LAR. In further characterizing this activation phenomenon, we reveal a novel role for the membrane-distal cytoplasmic PTP domain (D2) of PTPalpha: the direct intramolecular regulation of the activity of the membrane-proximal cytoplasmic PTP domain (D1). Binding of certain of these compounds to PTPalpha 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.
authors.affiliation: Departments of Biochemistry and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McCain
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Peter
authors.initials: P
authors.lastname: Nickel
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Annett
authors.initials: A
authors.lastname: Kreimeyer
authors.forename: Antonio
authors.initials: A
authors.lastname: Gagliardi
authors.forename: Delwood C
authors.initials: DC
authors.lastname: Collins
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry*; D002453:Cell Cycle; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008954:Models, Biological; D008956:Models, Chemical; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013498:Suramin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014357:Trypsin / Q000494:pharmacology; D015007:Yersinia / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000737:chemistry
chemical_list: D001425:Bacterial Outer Membrane Proteins; D004791:Enzyme Inhibitors; D013498:Suramin; C517004:CDC25A protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases; C067571:yopH protein, Yersinia; D014357:Trypsin