Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cell

Stephanie M. Stanford, Divya Krishnamurthy, Matthew D. Falk, Rossella Messina, Bikash Debnath, Sheng Li, Tong Liu, Roza Kazemi, Russell Dahl, Yantao He, Xiao Yu, Andrew C. Chan, Zhong-Yin Zhang, Amy M. Barrios, Virgil L. Woods, Nouri Neamati, Nunzio Bottini

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, is a critical regulator of signaling in T cells and recently emerged as a candidate target for therapy of autoimmune diseases. Here, by library screening, we identified a series of noncompetitive inhibitors of LYP that showed activity in primary T cells. Kinetic analysis confirmed that binding of the compounds to the phosphatase is nonmutually exclusive with respect to a known bidentate competitive inhibitor. The mechanism of action of the lead inhibitor compound 4e was studied by a combination of hydrogen/deuterium-exchange mass spectrometry and molecular modeling. The results suggest that the inhibitor interacts critically with a hydrophobic patch located outside the active site of the phosphatase. Targeting of secondary allosteric sites is viewed as a promising yet unexplored approach to develop pharmacological inhibitors of protein tyrosine phosphatases. Our novel scaffold could be a starting point to attempt development of "nonactive site" anti-LYP pharmacological agents.

Original languageEnglish
Pages (from-to)1640-1654
Number of pages15
JournalJournal of Medicinal Chemistry
Volume54
Issue number6
DOIs
StatePublished - Mar 24 2011

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Non-Receptor Type 22 Protein Tyrosine Phosphatase
Phosphoric Monoester Hydrolases
Human Activities
Tyrosine
Pharmacology
Allosteric Site
T-Lymphocytes
Protein Tyrosine Phosphatases
Deuterium
Autoimmune Diseases
Hydrogen
Mass Spectrometry
Catalytic Domain
Genes
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Stanford, S. M., Krishnamurthy, D., Falk, M. D., Messina, R., Debnath, B., Li, S., ... Bottini, N. (2011). Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cell. Journal of Medicinal Chemistry, 54(6), 1640-1654. https://doi.org/10.1021/jm101202j

Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cell. / Stanford, Stephanie M.; Krishnamurthy, Divya; Falk, Matthew D.; Messina, Rossella; Debnath, Bikash; Li, Sheng; Liu, Tong; Kazemi, Roza; Dahl, Russell; He, Yantao; Yu, Xiao; Chan, Andrew C.; Zhang, Zhong-Yin; Barrios, Amy M.; Woods, Virgil L.; Neamati, Nouri; Bottini, Nunzio.

In: Journal of Medicinal Chemistry, Vol. 54, No. 6, 24.03.2011, p. 1640-1654.

Research output: Contribution to journalArticle

Stanford, SM, Krishnamurthy, D, Falk, MD, Messina, R, Debnath, B, Li, S, Liu, T, Kazemi, R, Dahl, R, He, Y, Yu, X, Chan, AC, Zhang, Z-Y, Barrios, AM, Woods, VL, Neamati, N & Bottini, N 2011, 'Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cell', Journal of Medicinal Chemistry, vol. 54, no. 6, pp. 1640-1654. https://doi.org/10.1021/jm101202j
Stanford, Stephanie M. ; Krishnamurthy, Divya ; Falk, Matthew D. ; Messina, Rossella ; Debnath, Bikash ; Li, Sheng ; Liu, Tong ; Kazemi, Roza ; Dahl, Russell ; He, Yantao ; Yu, Xiao ; Chan, Andrew C. ; Zhang, Zhong-Yin ; Barrios, Amy M. ; Woods, Virgil L. ; Neamati, Nouri ; Bottini, Nunzio. / Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cell. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 6. pp. 1640-1654.
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