PS315, binding at the PIF-pocket, induces a displacement of the active site residue Lys111, thereby inhibiting the activity of aPKCs by allosterically affecting the catalytic mechanism of the kinase. Preincubation of U937 cells with 5 μM PS315 inhibits TNF-α caused NF-κB activation by 74%, whereas complete inhibition is observed with 10 μM PS315. The small allosteric inhibitor PS315 and the N-terminal region of aPKC both act directly on the PIF-pocket on-off switch[1].