A High-Throughput Screen for Receptor Protein Tyrosine Phosphatase–γ Selective Inhibitors

Protein tyrosine phosphatase-g (PTP-g) is a receptor-like PTP whose biological function is poorly understood. A recent mouse PTP-g genetic deletion model associated the loss of PTP-g 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-g (RPTP-g) 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-g. A subset of the BMS diverse compound collection was screened and several compounds identified as RPTP-g inhibitors in the assay. After chemical triage and clustering, compounds were assessed for potency and selectivity by IC 50 determination with RPTP-g and two other phosphatases, PTP-1B and CD45. One hundred twenty-nine RPTP-g 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 che- motype for the initiation of a medicinal chemistry program. (Journal of Biomolecular Screening 2011:000-000)