An article 1 that I really found fascinating and potentially with substantial consequences in the way we think about the “activity” of compounds and the way we set up biological screens is the work from AZ discussing selective inhibitors of kinase substrate activation. Specifically the AZ team have identified ATP competitive inhibitors of p38 kinase, which as with many kinases has multiple substrates, that selectivity inhibit the phosphorylation of one substrate over another. Compounds from two chemical series were identified and the authors showed that the substrate selectivity was due to a specific polar interaction. The key to identifying these compounds was the use of the endogenous target and off-target substrates in the primary screen rather than an artificial substrate that virtually everyone else in the field has been using. I am not aware of this approach being used previously but will be happy to be proved wrong.
- J. G. Cumming et al J. Med. Chem., 2015, 58 (1), 278–293