Strategies for targets sensitive to Redox Cycling Compounds

Pan-assay Interference Compounds (PAINS) are often, if not always, present in screening libraries. The activity of these compounds is not dependant on a specific, drug-like interaction between the molecules and the target yet they often appear active in screening. Here we will be focusing on a specific class of PAINS compounds which are the Redox Cycling Compounds (RCCs). RCCs are able to generate reactive oxygen species (H2O2 and O2-) in buffers containing a strong reducing agent. The reactive oxygen species indirectly inhibit catalytic activity of many enzymes, resulting in an inflated screening hit rate which require extra, often critical resources in order to develop and implement follow up assays to distinguish RCCs from real hits. Deubiquitinase enzymes (DUBs) are a class of targets (cysteine protease proteins) that have been reported to be sensitive to RCCs. As part of our alliance with Forma Therapeutics on Drug Discovery program identifying DUBs inhibitors, we have reviewed our approach and have evaluated the occurance of RCCs in our own library.

Poster presented by Cristina Alli at ELRIG Drug Discovery 2015 (Telford, UK)

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