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A low success rate of drug candidates reflects that existing drug screening formats are very far from optimal. One of the biggest problems with the enzyme inhibitors targeting the enzyme active site is that they very likely will inhibit unknown enzymes of the same structural group resulting in unpredicted side effects. For example, there are more than 60 alpha-ketoglutarate dependent non-heme iron dioxygenases in human genome: the known representatives (HIF hydroxylase, histone demethylase, cytosine hydroxylase, etc) play very important roles in the cell, however, the functions of the majority of these enzymes (>50) are unknown. Active sites share a catalytic triad with iron, and developing specific inhibitors requires a control run against at least all known enzymes in the group. A very popular trend in drug discovery is inhibiting ubiquitinylation of a protein of interest. Ubiquitin ligase 3, the terminal enzyme of the ubiquitinylation complexes, may have up to 60 protein clients, and thus E3 ligase inhibition at the active site will prevent ubiquitination of all 60 client substrates. The new trend in drug discovery is to disrupt a specific protein-protein interaction or, vice versa, to stabilize protein-protein interaction within multiprotein complexes with small molecules. New strategic approaches to this problem suitable for high throughput drug screening format have been developed: Thermofluor technology (exclusively licensed by Johnson & Johnson) successfully applied to develop a p53 stabilizer, and brand new method of affinity selection mass-sprectrometry (AS-MS), which enables rapid screen of million compound libraries, applied by Merck to find a HIF prolyl hydroxylase inhibitor. In vitro assays usually yield drug candidates with orders of magnitude lower potency when tested under in vivo conditions. In many cases such a drop in potency originates from the need to compete with intracellular metabolites/proteins absent from the in vitro assay mixture. Our lab develops a novel experimental approach based on the construction of cell-based reporters representing the minimum portion of transcription factor regulated by ubiquitinylation bound to firefly luciferase. Cell-based screens have an advantage of selecting potent, cell-permeable and non-toxic drug candidates right away from the beginning. The results of high throughput screens for HIF prolyl hydroxylase inhibitors and non-electrophilic Nrf2 activators will be presented.