A different take on kinase inhibitors and selective inhibition of substrate phosphorylation

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.

  1. J. G. Cumming et al J. Med. Chem., 2015, 58 (1), 278–293

Aryl halides

A couple of papers looking at different aspects of halogens in drug discovery. Firstly 1 the frequency of para-substituted chlorophenyl compounds both in commercial reagents and in marketed drugs is disproportionately high relative to ortho- or meta- substitution. The authors speculate that the high frequency of para-chlorophenyl in drugs may reflect both reagent availability and the use of Topliss decision tree strategies for substituent selection. Interestingly meta-substitution is quite rare while ortho is comparatively ore common at about 25% the frequency of a para-chlorosubstituent certainly conformational effects will be playing a big role in this. Of course introducing an ortho-substituent is often the reaction that fails in array chemistry requiring bespoke synthesis.

Halogen bonding is getting an increasing profile thus scoring functions to recognise opportunities for halogen bonding are valuable 2. Perhaps an ortho chloro substituent has greater difficulty in achieving a good alignment for a robust interaction although that doesn’t explain the infrequent occurrence of meta-substituted arylchlorides.

  1. Understanding Our Love Affair with p-Chlorophenyl: Present Day Implications from Historical Biases of Reagent Selection Dean G. Brown, Moriah M. Gagnon and Jonas Boström J. Med. Chem., Article ASAP DOI: 10.1021/jm501894t Publication Date (Web): February 19, 2015 Copyright © 2015, American Chemical Society http://pubs.acs.org/doi/abs/10.1021/jm501894t
  2. Evaluating the Potential of Halogen Bonding in Molecular Design: Automated Scaffold Decoration Using the New Scoring Function XBScore Markus O. Zimmermann, Andreas Lange and Frank M. Boeckler J. Chem. Inf. Model., Article ASAP DOI: 10.1021/ci5007118 Publication Date (Web): February 19, 2015 Copyright © 2015, American Chemical Society, http://pubs.acs.org/doi/abs/10.1021/ci5007118