Switch pocket inhibitors

BIRB-796 binds to the inactive DFG-out conformation of P38 and has been tested in Phase II clinical trials for rheumatoid arthritis, Crohn s disease and psoriasis but was withdrawn, possibly due to elevation in liver enzymes.16 A key aim of Deciphera5s work was to synthesise compounds which interacted more specifically with the switch pocket amino acids to remove the need for the 

The synthesised compound, DP-802 (11), demonstrated potent binding to the unphosphorylated protein with an IC50 of 9 nM, with thermal melt studies 

It will be interesting to observe how these reported benefits from the exploitation of these switch pocket residues may translate into advantages in the clinic. 

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