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, Zhong-Yin Zhang

Research output: Contribution to journalArticle

52 Citations (Scopus)

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, PTPα, 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 PTPα. Surprisingly, we found that a significant number of these compounds activated the receptor-like phosphatases, PTPα and LAR. In further characterizing this activation phenomenon, we reveal a novel role for the membrane-distal cytoplasmic PTP domain (D2) of PTPα: the direct intramolecular regulation of the activity of the membrane-proximal cytoplasmic PTP domain (D1). Binding of certain of these compounds to PTPα 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.

Original languageEnglish (US)
Pages (from-to)14713-14725
Number of pages13
JournalJournal of Biological Chemistry
Volume279
Issue number15
DOIs
StatePublished - Apr 9 2004
Externally publishedYes

Fingerprint

Suramin
Protein Tyrosine Phosphatases
Derivatives
Phosphoric Monoester Hydrolases
Inhibitory Concentration 50
cdc25 Phosphatases
Cell Membrane
Membranes
Yersinia
Plague
Phosphatases
Virulence Factors
Cell Cycle

ASJC Scopus subject areas

  • Biochemistry

Cite this

McCain, D. F., Wu, L., Nickel, P., Kassack, M. U., Kreimeyer, A., Gagliardi, A., ... Zhang, Z-Y. (2004). Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases. Journal of Biological Chemistry, 279(15), 14713-14725. https://doi.org/10.1074/jbc.M312488200

Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases. / McCain, Daniel F.; Wu, Li; Nickel, Peter; Kassack, Matthias U.; Kreimeyer, Annett; Gagliardi, Antonio; Collins, Delwood C.; Zhang, Zhong-Yin.

In: Journal of Biological Chemistry, Vol. 279, No. 15, 09.04.2004, p. 14713-14725.

Research output: Contribution to journalArticle

McCain, DF, Wu, L, Nickel, P, Kassack, MU, Kreimeyer, A, Gagliardi, A, Collins, DC & Zhang, Z-Y 2004, 'Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases', Journal of Biological Chemistry, vol. 279, no. 15, pp. 14713-14725. https://doi.org/10.1074/jbc.M312488200
McCain DF, Wu L, Nickel P, Kassack MU, Kreimeyer A, Gagliardi A et al. Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases. Journal of Biological Chemistry. 2004 Apr 9;279(15):14713-14725. https://doi.org/10.1074/jbc.M312488200
McCain, Daniel F. ; Wu, Li ; Nickel, Peter ; Kassack, Matthias U. ; Kreimeyer, Annett ; Gagliardi, Antonio ; Collins, Delwood C. ; Zhang, Zhong-Yin. / Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 15. pp. 14713-14725.
@article{58643de7e8df4055abdc607f98d3b987,
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, PTPα, 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 PTPα. Surprisingly, we found that a significant number of these compounds activated the receptor-like phosphatases, PTPα and LAR. In further characterizing this activation phenomenon, we reveal a novel role for the membrane-distal cytoplasmic PTP domain (D2) of PTPα: the direct intramolecular regulation of the activity of the membrane-proximal cytoplasmic PTP domain (D1). Binding of certain of these compounds to PTPα 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.",
author = "McCain, {Daniel F.} and Li Wu and Peter Nickel and Kassack, {Matthias U.} and Annett Kreimeyer and Antonio Gagliardi and Collins, {Delwood C.} and Zhong-Yin Zhang",
year = "2004",
month = "4",
day = "9",
doi = "10.1074/jbc.M312488200",
language = "English (US)",
volume = "279",
pages = "14713--14725",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "15",

}

TY - JOUR

T1 - Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases

AU - McCain, Daniel F.

AU - Wu, Li

AU - Nickel, Peter

AU - Kassack, Matthias U.

AU - Kreimeyer, Annett

AU - Gagliardi, Antonio

AU - Collins, Delwood C.

AU - Zhang, Zhong-Yin

PY - 2004/4/9

Y1 - 2004/4/9

N2 - 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, PTPα, 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 PTPα. Surprisingly, we found that a significant number of these compounds activated the receptor-like phosphatases, PTPα and LAR. In further characterizing this activation phenomenon, we reveal a novel role for the membrane-distal cytoplasmic PTP domain (D2) of PTPα: the direct intramolecular regulation of the activity of the membrane-proximal cytoplasmic PTP domain (D1). Binding of certain of these compounds to PTPα 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.

AB - 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, PTPα, 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 PTPα. Surprisingly, we found that a significant number of these compounds activated the receptor-like phosphatases, PTPα and LAR. In further characterizing this activation phenomenon, we reveal a novel role for the membrane-distal cytoplasmic PTP domain (D2) of PTPα: the direct intramolecular regulation of the activity of the membrane-proximal cytoplasmic PTP domain (D1). Binding of certain of these compounds to PTPα 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.

UR - http://www.scopus.com/inward/record.url?scp=2442609929&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2442609929&partnerID=8YFLogxK

U2 - 10.1074/jbc.M312488200

DO - 10.1074/jbc.M312488200

M3 - Article

VL - 279

SP - 14713

EP - 14725

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 15

ER -