Characterisation of p38 switch pocket inhibitors


Doramapimod (BIRB-796), from Boehringer Ingelheim, was the first reported  inhibitor of p38 which did not bind to the canonical ATP site.  This opened up the prospect of allosteric inhibition of kinases as a viable approach to identifying novel drug candidates.

This letter from the Abbott laboratories reports their efforts to further characterise compounds of this class.  They prepared a set of compounds targetting the so-called ‘switch pocket’ of p38 (a pocket which is thought to extend beyond the ‘BIRB-site’ into a region adjacent to the ATP binding site when the protein is in the DFG-out conformation) and evaluated their binding kinetics and kinome inhibition profiles.   They show that inhibitors of this type have very different binding kinetics to those of ATP-site inhibitors and interestingly also demonstrate that within the class of compounds explored there are potential possibilities for tuning the selectivity across the kinome.  This is a very interesting, emerging area and no doubt we’ll see more of this type of compound in the future.

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