title: Inhibition of the lymphoid tyrosine phosphatase: the effect of zinc(II) ions and chelating ligand fragments on enzymatic activity.
abstract: A 96-member chelator fragment library (CFL-1.1) was screened to identify inhibitors of the lymphoid tyrosine phosphatase in the absence and presence of zinc acetate. Fragments that inhibit LYP activity more potently in the presence of zinc, fragments that rescue LYP activity in the presence of inhibitory concentrations of zinc, and fragments that inhibit LYP activity independent of zinc concentration were identified. Of these, 1,2-dihydroxynaphthalene was the most potent inhibitor with an IC50 value of 2.52±0.06 μM after 2 h of incubation. LYP inhibition by 1,2-dihydroxynaphthalene was very similar to inhibition by 1,2-naphthoquinone (IC50=1.10±0.03 µM), indicating that the oxidized quinone species is likely the active inhibitor. The inhibition was time-dependent, consistent with covalent modification of the enzyme.
authors.affiliation: Department of Medicinal Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, USA.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Thorson
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Puerta
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
authors.affiliation: Department of Medicinal Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, USA. Electronic address: Amy.Barrios@Utah.edu.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Barrios
mesh_terms: D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007477:Ions / Q000737:chemistry; D015394:Molecular Structure; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007477:Ions; D017027:Protein Tyrosine Phosphatases; D015032:Zinc
keywords: Chelator fragment library; Enzyme inhibitors; Protein tyrosine phosphatase