Arylstibonic acids are potent and isoform-selective inhibitors of Cdc25a and Cdc25b phosphatases

Lok Hang Mak; Jessica Knott; Katherine A. Scott; Claire Scott; Gillian F. Whyte; Yu Ye; David J. Mann; Oscar Ces; James Stivers; Rudiger Woscholski

doi:10.1016/j.bmc.2012.05.040

Arylstibonic acids are potent and isoform-selective inhibitors of Cdc25a and Cdc25b phosphatases

Lok Hang Mak, Jessica Knott, Katherine A. Scott, Claire Scott, Gillian F. Whyte, Yu Ye, David J. Mann, Oscar Ces, James Stivers, Rudiger Woscholski

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Arylstibonates structurally resemble phosphotyrosine side chains in proteins and here we addressed the ability of such compounds to act as inhibitors of a panel of mammalian tyrosine and dual-specificity phosphatases. Two arylstibonates both possessing a carboxylate side chain were identified as potent inhibitors of the protein tyrosine phosphatase PTP-ß. In addition, they inhibited the dual-specificity, cell cycle regulatory phosphatases Cdc25a and Cdc25b with sub-micromolar potency. However, the Cdc25c phosphatase was not affected demonstrating that arylstibonates may be viable leads from which to develop isoform specific Cdc25 inhibitors.

Original language	English (US)
Pages (from-to)	4371-4376
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	14
DOIs	https://doi.org/10.1016/j.bmc.2012.05.040
State	Published - Jul 15 2012

Keywords

Arylstibonic acids
Cdc25 inhibitor
Protein tyrosine phosphatase

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2012.05.040

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Arylstibonic acids are potent and isoform-selective inhibitors of Cdc25a and Cdc25b phosphatases. / Mak, Lok Hang; Knott, Jessica; Scott, Katherine A.; Scott, Claire; Whyte, Gillian F.; Ye, Yu; Mann, David J.; Ces, Oscar; Stivers, James; Woscholski, Rudiger.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 14, 15.07.2012, p. 4371-4376.

Research output: Contribution to journal › Article › peer-review

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abstract = "Arylstibonates structurally resemble phosphotyrosine side chains in proteins and here we addressed the ability of such compounds to act as inhibitors of a panel of mammalian tyrosine and dual-specificity phosphatases. Two arylstibonates both possessing a carboxylate side chain were identified as potent inhibitors of the protein tyrosine phosphatase PTP-{\ss}. In addition, they inhibited the dual-specificity, cell cycle regulatory phosphatases Cdc25a and Cdc25b with sub-micromolar potency. However, the Cdc25c phosphatase was not affected demonstrating that arylstibonates may be viable leads from which to develop isoform specific Cdc25 inhibitors.",

keywords = "Arylstibonic acids, Cdc25 inhibitor, Protein tyrosine phosphatase",

author = "Mak, {Lok Hang} and Jessica Knott and Scott, {Katherine A.} and Claire Scott and Whyte, {Gillian F.} and Yu Ye and Mann, {David J.} and Oscar Ces and James Stivers and Rudiger Woscholski",

note = "Funding Information: We thank Bob Shoemaker and Rhone Akee and the Developmental Therapeutics Program at the National Cancer Institute, Frederick Maryland for providing the arylstibonic acid small molecule library. We would also like to thank Jack E. Dixon (University of California at San Diego) for the generous gift of the expression plasmid of PTPMT1. This work was supported by an EPSRC Centre for Doctoral Training Studentship from the Institute of Chemical Biology (Imperial College London) awarded to J.K., Cancer research UK (D.M.) and a NIH Grants GM068626 and GM056834 to J.T.S. ",

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AU - Knott, Jessica

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AU - Scott, Claire

AU - Whyte, Gillian F.

AU - Ye, Yu

AU - Mann, David J.

AU - Ces, Oscar

AU - Stivers, James

AU - Woscholski, Rudiger

N1 - Funding Information: We thank Bob Shoemaker and Rhone Akee and the Developmental Therapeutics Program at the National Cancer Institute, Frederick Maryland for providing the arylstibonic acid small molecule library. We would also like to thank Jack E. Dixon (University of California at San Diego) for the generous gift of the expression plasmid of PTPMT1. This work was supported by an EPSRC Centre for Doctoral Training Studentship from the Institute of Chemical Biology (Imperial College London) awarded to J.K., Cancer research UK (D.M.) and a NIH Grants GM068626 and GM056834 to J.T.S.

PY - 2012/7/15

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AB - Arylstibonates structurally resemble phosphotyrosine side chains in proteins and here we addressed the ability of such compounds to act as inhibitors of a panel of mammalian tyrosine and dual-specificity phosphatases. Two arylstibonates both possessing a carboxylate side chain were identified as potent inhibitors of the protein tyrosine phosphatase PTP-ß. In addition, they inhibited the dual-specificity, cell cycle regulatory phosphatases Cdc25a and Cdc25b with sub-micromolar potency. However, the Cdc25c phosphatase was not affected demonstrating that arylstibonates may be viable leads from which to develop isoform specific Cdc25 inhibitors.

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Arylstibonic acids are potent and isoform-selective inhibitors of Cdc25a and Cdc25b phosphatases

Abstract

Keywords

ASJC Scopus subject areas

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