title: A high-throughput screen for receptor protein tyrosine phosphatase-gamma selective inhibitors.
abstract: Protein tyrosine phosphatase-γ (PTP-γ) is a receptor-like PTP whose biological function is poorly understood. A recent mouse PTP-γ genetic deletion model associated the loss of PTP-γ gene expression with a potential antidepressant phenotype. This led the authors to screen a subset of the Bristol-Myers Squibb (BMS) compound collection to identify selective small-molecule inhibitors of receptor-like PTP-γ (RPTP-γ) for use in evaluating enzyme function in vivo. Here, they report the design of a high-throughput fluorescence resonance energy transfer (FRET) assay based on the Z'-LYTE technology to screen for inhibitors of RPTP-γ. A subset of the BMS diverse compound collection was screened and several compounds identified as RPTP-γ inhibitors in the assay. After chemical triage and clustering, compounds were assessed for potency and selectivity by IC(50) determination with RPTP-γ and two other phosphatases, PTP-1B and CD45. One hundred twenty-nine RPTP-γ selective (defined as IC(50) value greater than 5- to 10-fold over PTP-1B and CD45) inhibitors were identified and prioritized for evaluation. One of these hits, 3-(3, 4-dichlorobenzylthio) thiophene-2-carboxylic acid, was the primary chemotype for the initiation of a medicinal chemistry program.
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, USA. kingsley.appiah@bms.com
authors.forename: Kingsley K
authors.initials: KK
authors.lastname: Appiah
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kostich
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Gerritz
authors.forename: Yanling
authors.initials: Y
authors.lastname: Huang
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hamman
authors.forename: Jason
authors.initials: J
authors.lastname: Allen
authors.forename: Wandong
authors.initials: W
authors.lastname: Zhang
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lanthorn
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.forename: Ryan
authors.initials: R
authors.lastname: Westphal
authors.forename: Martyn N
authors.initials: MN
authors.lastname: Banks
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: O'Connell
mesh_terms: D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D004795:Enzyme Stability / Q000187:drug effects; D057166:High-Throughput Screening Assays; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D012107:Research Design; D012680:Sensitivity and Specificity; D012997:Solvents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D012997:Solvents; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D004121:Dimethyl Sulfoxide