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.
Checler
Frédéric
F
Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097 du CNRS, 660 route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France. checler@ipmc.cnrs.fr.
Frédéric
Checler
C
Alves da Costa
Cristine
C
Cristine
Alves da Costa
Ada C
Ayral
Erwan
E
Erwan
Ayral
A
Andrau
David
D
David
Andrau
A
Dumanchin
Cécile
C
Cécile
Dumanchin
D
Farzan
Michael
M
Michael
Farzan
F
Hernandez
Jean-François
JF
Jean-François
Hernandez
H
Martinez
J
J
Lefranc-Jullien
Solveig
S
Solveig
Lefranc-Jullien
LJ
Marambaud
Philippe
P
Philippe
Marambaud
M
Pasini
Andrea
A
Andrea
Pasini
P
Petit
Agnès
A
Agnès
Petit
P
Phiel
Christopher
C
Christopher
Phiel
P
Robert
Philippe
P
Philippe
Robert
R
St George-Hyslop
Peter
P
Peter
St George-Hyslop
SG
Wilk
Sherwin
S
Sherwin
Wilk
W
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