PI3Kdelta is a lipid kinase, primarily expressed in leukocytes, that plays a key role in immune cell signalling. It is activated across a broad range of cell types in response to multiple triggers relevant to respiratory disease, including allergens, smoke, viruses and inflammatory cytokines. We previously disclosed nemiralisib (GSK2269557) and related PI3Kdelta selective inhibitors that were designed for inhaled delivery as potential therapeutic treatments to modulate the inflammatory processes leading to exacerbations associated with both asthma and COPD. Here we present hypotheses for the high PI3K isoform selectivity achieved for nemiralisib, discuss how modelling techniques and crystallography enhanced our understanding and show how learnings were applied to subsequent chemical templates.

Exploration and enhancement of PI3Kdelta selective compounds: The discovery of Nemiralisib and beyond

255th National Meeting (2018)

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