JLK inhibitors: isocoumarin compounds as putative probes to selectively target the gamma-secretase pathway.
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.
Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097 du CNRS, 660 route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France. checler@ipmc.cnrs.fr.
Frédéric
F
Checler
Checler
C
Frédéric
Cristine
C
Alves da Costa
Alves da Costa
Ada C
Cristine
Erwan
E
Ayral
Ayral
A
Erwan
David
D
Andrau
Andrau
A
David
Cécile
C
Dumanchin
Dumanchin
D
Cécile
Michael
M
Farzan
Farzan
F
Michael
Jean-François
JF
Hernandez
Hernandez
H
Jean-François
J
J
Martinez
Solveig
S
Lefranc-Jullien
Lefranc-Jullien
LJ
Solveig
Philippe
P
Marambaud
Marambaud
M
Philippe
Andrea
A
Pasini
Pasini
P
Andrea
Agnès
A
Petit
Petit
P
Agnès
Christopher
C
Phiel
Phiel
P
Christopher
Philippe
P
Robert
Robert
R
Philippe
Peter
P
St George-Hyslop
St George-Hyslop
SG
Peter
Sherwin
S
Wilk
Wilk
W
Sherwin
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D003374:Coumarins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D015335:Molecular Probes
D016229:Amyloid beta-Peptides; D003374:Coumarins; D004791:Enzyme Inhibitors; D015335:Molecular Probes; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human