Programme : Back to Dr Cristina Alli

Strategies for targets sensitive to Redox Cycling Compounds


Cristina Alli, Suzanne Grooby, Fabrice Turlais and Sheila McLoughlin

Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.

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 1-2 yet they often appear active in screen. In this report 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 1/9. Deubiquitinase enzymes (DUBs) are a class of targets (cysteine protease proteins) that have been reported to be sensitive to RCCs 3. 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. This poster will describe our process and some our thoughts for the future.

1. Baell et al, J. ACS Med. Chem. Lett., 2015, 6 (3), pp 229–234
2. Baell et al, Nature, 2014, 153, pp 481–483
3. Glague et al, Nature, 2013, 492 , pp 49–50
4. Johnston et al, Curr Opin Chem Biol, 2011, 15(1), pp 174-182
5. Johnston et al, Assay and Drug Development Discovery, 2008, 6 (4), pp 505–518
6. Johnston et al, Assay and Drug Development Technologies, 2007, 5, pp 319–332
7. Johnston et al, Assay and Drug Development Technology, 2009, 7, pp 250–265
8. Soares et al, Assay and Drug Development Discovery, 2010, 8 (2), pp 152–174
9. Smith et al, Arch Biochem Biophys, 2002, 399 (2), pp 195-205
10. Lor et al, Journal of Biomolecular Screening, 2007, 12 (6), pp 881–890
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