This talk will describe a collaboration project between GlaxoSmithKline and Astex Pharmaceuticals. Disrupting the KEAP1:NRF2 interaction to release the transcription factor NRF2 is a potential therapeutic intervention for diseases involving chronic oxidative stress. Through a successful fragment-based screening approach, we developed a series of highly potent inhibitors of the KEAP1:NRF2 interaction. It is well known that attrition in drug discovery projects either preclinically or beyond, can be caused by multiple factors which are hard to predict in the earlier stages of the projects. The best way to increase the chances of success is to deliver multiple series so that if a series-wide problem arises, then there are options to continue moving forward. To this end, we used the pharmacophoric information from the original fragment screen to search the GSK compound collection. This resulted in pyrazole carboxylic acid hits that could be enhanced using structure-based drug design. Information from the elaboration of the first series could then be applied to these hits, expediting the delivery of a second potent and novel series for lead optimisation.

Fragment-guided discovery of pyrazole carboxylic acid inhibitors of the KEAP1:NRF2 protein-protein interaction

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