Discovery of a Novel Series of Inhibitors of Lymphoid Tyrosine Phosphatase with Activity in Human T Cells

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Author list: Stanford SM, Krishnamurthy D, Falk MD, Messina R, Debnath B, Li S, Liu T, Kazemi R, Dahl R, He YT, Yu XA, Chan AC, Zhang ZY, Barrios AM, Woods VL, Neamati N, Bottini N
Publisher: American Chemical Society
Publication year: 2011
Volume number: 54
Issue number: 6
Start page: 1640
End page: 1654
Number of pages: 15
ISSN: 0022-2623
Languages: English-Great Britain (EN-GB)


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.


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Last updated on 2019-23-08 at 11:15