JLK inhibitors: Isocoumarin compounds as putative probes to selectively target the γ-secretase pathway

Alzheimer's disease is characterized by the extracellular deposition of the amyloid β-peptide that derives from its precursor βAPP by sequential actions of β- and γ- secretases, respectively. Recent studies aimed at identifying these enzymes have been reported as it is thougth that their inhibition should hopefully lead to reduce Aβ load in the AD brains. β-secretase seems to be due to BACE1, a novel membrane-bound aspartyl protease. γ-secretase identification is still a matter of controversy. Invalidation of presenilin genes was reported to impair both γ-secretase-mediated Aβ production and Notch cleavage leading to NICD production. This observation together with another biochemical and pharmacological evidences led to suggest that presenilins could be the genuine long-searched γ-secretase that would be responsible for both APP and Notch cleavages. We have designed novel non peptidic potential inhibitors of γ-secretase (referred to as JLK inhibitors) and examined their ability to prevent Aβ40 and Aβ42 secretions as well as NICD production. Three out of a series of these agents drastically lower the recoveries of both Aβ40 and Aβ42 produced by βAPP-expressing cell lines and concomitantly protect intracellular C99 and C83 recoveries. These inhibitors also prevent Aβ40/42 productions by C99-expressing cells. Interestingly, these inhibitors were totally unable to affect the ΔENotch cleavage leading to NICD generation. Here, we also further characterize the pharmacological properties and specificity of these JLK inhibitors.