Selective inhibitors of the PSEN1-gamma-secretase complex.
inhibitors
medicinal chemistry
selectivity
therapy
ƴ-secretase
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
31
01
2023
revised:
28
04
2023
accepted:
02
05
2023
medline:
28
6
2023
pubmed:
11
5
2023
entrez:
10
5
2023
Statut:
ppublish
Résumé
Clinical development of γ-secretases, a family of intramembrane cleaving proteases, as therapeutic targets for a variety of disorders including cancer and Alzheimer's disease was aborted because of serious mechanism-based side effects in the phase III trials of unselective inhibitors. Selective inhibition of specific γ-secretase complexes, containing either PSEN1 or PSEN2 as the catalytic subunit and APH1A or APH1B as supporting subunits, does provide a feasible therapeutic window in preclinical models of these disorders. We explore here the pharmacophoric features required for PSEN1 versus PSEN2 selective inhibition. We synthesized a series of brain penetrant 2-azabicyclo[2,2,2]octane sulfonamides and identified a compound with low nanomolar potency and high selectivity (>250-fold) toward the PSEN1-APH1B subcomplex versus PSEN2 subcomplexes. We used modeling and site-directed mutagenesis to identify critical amino acids along the entry part of this inhibitor into the catalytic site of PSEN1. Specific targeting one of the different γ-secretase complexes might provide safer drugs in the future.
Identifiants
pubmed: 37164155
pii: S0021-9258(23)01822-7
doi: 10.1016/j.jbc.2023.104794
pmc: PMC10318456
pii:
doi:
Substances chimiques
Amyloid Precursor Protein Secretases
EC 3.4.-
Presenilin-1
0
PSEN1 protein, human
0
PSEN2 protein, human
0
APH1A protein, human
EC 3.4.-
APH1B protein, human
EC 3.4.-
Multiprotein Complexes
0
Sulfonamides
0
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104794Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest L. S., R. N., L. P. B., M. M., V. G., D. T., F. B., M. D., E. F., G. T., P. W. M. R., and H. J. M. G. declare no competing interest. B. D. S. is or has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie, and other companies. B. D. S is also a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics. B. D. S. holds the Bax-Vanluffelen Chair for AD.
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