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

42 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Stanford, S. M., Krishnamurthy, D., Falk, M. D., Messina, R., Debnath, B., Li, S., Liu, T., Kazemi, R., Dahl, R., He, Y., Yu, X., Chan, A. C., Zhang, Z. Y., Barrios, A. M., Woods, V. L., 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, 54(6), 1640-1654. https://doi.org/10.1021/jm101202j