title: Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cells.
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.
authors.affiliation: Institute for Genetic Medicine, University of Southern California, Los Angeles, California 90033, United States.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.forename: Divya
authors.initials: D
authors.lastname: Krishnamurthy
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Falk
authors.forename: Rossella
authors.initials: R
authors.lastname: Messina
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Roza
authors.initials: R
authors.lastname: Kazemi
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Amy M
authors.initials: AM
authors.lastname: Barrios
authors.forename: Virgil L
authors.initials: VL
authors.lastname: Woods
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
mesh_terms: D000495:Allosteric Site; D000818:Animals; D020134:Catalytic Domain; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D041961:Deuterium Exchange Measurement; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D015363:Quinolones; D054852:Small Molecule Libraries; D013777:Tetrazoles; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse