JLK Inhibitors: Isocoumarin Compounds as Putative Probes to Selectively Target the γ-Secretase Pathway

Abstract

Alzheimer's disease is characterized by the extracellular deposition of the amyloid beta-peptide that derives from its precursor betaAPP by sequential actions of beta- and gamma- secretases, respectively. Recent studies aimed at identifying these enzymes have been reported as it is thougth that their inhibition should hopefully lead to reduce Abeta load in the AD brains. beta-secretase seems to be due to BACE1, a novel membrane-bound aspartyl protease. gamma-secretase identification is still a matter of controversy. Invalidation of presenilin genes was reported to impair both gamma-secretase-mediated Abeta 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 gamma-secretase that would be responsible for both APP and Notch cleavages. We have designed novel non peptidic potential inhibitors of gamma-secretase (referred to as JLK inhibitors) and examined their ability to prevent Abeta40 and Abeta42 secretions as well as NICD production. Three out of a series of these agents drastically lower the recoveries of both Abeta40 and Abeta42 produced by betaAPP-expressing cell lines and concomitantly protect intracellular C99 and C83 recoveries. These inhibitors also prevent Abeta40/42 productions by C99-expressing cells. Interestingly, these inhibitors were totally unable to affect the DeltaENotch cleavage leading to NICD generation. Here, we also further characterize the pharmacological properties and specificity of these JLK inhibitors.

Computer-Aided Drug Design Applied to Beta and Gamma Secretase Inhibitors-Perspectives for New Alzheimer Disease Therapy

“…Some of these agents drastically reduced both Aβ40 and Aβ42 level produced by betaAPP-expressing cell lines and also protected intracellular C99 and C83 recoveries. Very important, these inhibitors have not affected the DeltaENotch cleavage leading to NICD generation [110]. the 3D structure of the beta and game secretases (for AD pathology case) active site and their inhibitors, respectively.…”

“…Also, the development of a novel series of 4-aryl, 4-phenylsulfonyl cyclohexananonederived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease were described. Frederic C. and his colleagues have designed novel non peptidic potential inhibitors of gamma-secretase (one of them namely JLK) [110] and also, have examined their ability to prevent Aβ40 and Aβ42 secretions as well as NICD production. Some of these agents drastically reduced both Aβ40 and Aβ42 level produced by betaAPP-expressing cell lines and also protected intracellular C99 and C83 recoveries.…”

Polyketides as Secondary Metabolites from the Genus Aspergillus

“…Aspergillus -derived isocoumarins ( Figure 7 ) are a class of phenolic compounds usually containing hydroxyl group(s) and display various pharmacological properties, including antimicrobial, anti-inflammatory, cytotoxic activities and inhibitory effects on serine protease and gamma-secretase [ 61 , 62 , 63 ]. Chemical investigation of an Indo-Pacific marine sponge-derived A. ochraceus afforded a new dihydroisocoumarin, (−)-( R )-mellein ( 102 ), which exhibited a broad spectrum of antifungal and antioomycetes activities [ 64 ].…”