Identification of Chemical Lead Structures

To identify small molecule PTP lead structures, the most straightforward method is to mimic the natural substrate pTyr by making non-hydrolyzable analogs. Initial attempts in academia were very successful in developing model compounds as described below (Sect. 9.1). Since these compounds often showed poor or no cellular activity, most companies turned to high-throughput screening (HTS) in attempts to identify novel lead structures. At Novo Nordisk we used a scintillation proximity assay (SPA) with PTP1B and a biotinylated [33P]-radiolabeled peptide substrate corresponding to the activation loop of the insulin receptor tyrosine kinase. A substantial number of hits were identified in the screening. However, when analyzing these hit compounds in detail, as recommended below, most were eliminated as false positives. The compound that fulfilled most of our pre-defined selection criteria (see below) was 2-(oxalylamino)-benzoic acid, OBA (compound 1, Fig. 4; Andersen et al. 2000). This compound was found to share most of the

Fig. 4 Chemical lead structures identified by different strategies
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