JLK Isocoumarin Inhibitors: Selective γ-Secretase Inhibitors that Do Not Interfere with Notch Pathway In Vitro or In Vivo

γ-Secretase activity is involved in the generation of Aβ and therefore likely contributes to the pathology of Alzheimer's disease. Blocking this activity was seen as a major therapeutic target to slow down or arrest Aβ-related AD progression. This strategy seemed more doubtful when it was established that γ-secretase also targets other substrates including Notch, a particularly important transmembrane protein involved in vital functions, at both embryonic and adulthood stages. We have described previously new non-peptidic inhibitors able to selectively inhibit Aβ cellular production in vitro without altering Notch pathway. We show here that in vivo, these inhibitors do not alter the Notch pathway responsible for somitogenesis in the zebrafish embryo. In addition, we document further the selectivity of JLK inhibitors by showing that, unlike other described γ-secretase inhibitors, these agents do not affect E-cadherin processing. Finally, we establish that JLKs do not inhibit β-site APP cleaving enzymes (BACE) 1 and BACE2, α-secretase, the proteasome, and GSK3β kinase. Altogether, JLK inhibitors are the sole agents to date that are able to prevent Aβ production without triggering unwanted cleavages of other proteins.