JLK isocoumarin inhibitors: selective gamma-secretase inhibitors that do not interfere with notch pathway in vitro or in vivo.
gamma-Secretase activity is involved in the generation of Abeta 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 Abeta-related AD progression. This strategy seemed more doubtful when it was established that gamma-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 Abeta 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 gamma-secretase inhibitors, these agents do not affect E-cadherin processing. Finally, we establish that JLKs do not inhibit beta-site APP cleaving enzymes (BACE) 1 and BACE2, alpha-secretase, the proteasome, and GSK3beta kinase. Altogether, JLK inhibitors are the sole agents to date that are able to prevent Abeta production without triggering unwanted cleavages of other proteins.
Petit
A
A
Institut de Pharmacologie, Moléculaire et Cellulaire, CNRS, UMR6097, Valbonne, France.
Pasini
A
A
Alves Da Costa
C
C
Ayral
E
E
Hernandez
J F
JF
Dumanchin-Njock
C
C
Phiel
C J
CJ
Marambaud
P
P
Wilk
S
S
Farzan
M
M
Fulcrand
P
P
Martinez
J
J
Andrau
D
D
Checler
F
F
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002219:Carbamates / Q000032:analysis / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004151:Dipeptides / Q000032:analysis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects; D004625:Embryo, Nonmammalian; D010450:Endopeptidases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007668:Kidney; D008565:Membrane Proteins / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D051880:Receptors, Notch; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014280:Triglycerides / Q000494:pharmacology; D015027:Zebrafish; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D000925:Anticoagulants; D015820:Cadherins; D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D051880:Receptors, Notch; D014280:Triglycerides; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; D046988:Proteasome Endopeptidase Complex