ArticleThe Journal of biological chemistry2023
Selective inhibitors of the PSEN1-gamma-secretase complex.
Article in The Journal of biological chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- Targeting mannosylation of nicastrin N-glycans attenuates γ-secretase activity and notch-dependent leukemia progression.The Journal of clinical investigation · 2026Article
- Mining Alzheimer's Interactomes, Macromolecular Complexes and Pathways for Drug Discovery.Proteomics · 2025Review
- Daurisoline Inhibits Progression of Triple-Negative Breast Cancer by Regulating the γ-Secretase/Notch Axis.Biomolecules & therapeutics · 2025Article
- New Research on Biomarkers in Alzheimer's Continuum.Reviews on recent clinical trials · 2025Review
- Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson's Disease Dementia (PDD).Neurotoxicity research · 2024Article
- ADME profiling, molecular docking, DFT, and MEP analysis reveal cissamaline, cissamanine, and cissamdine fromRSC advances · 2024Article
- New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.The EMBO journal · 2024Review
- Navigating the Frontiers of Machine Learning in Neurodegenerative Disease Therapeutics.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Review
- γ-Secretase: once and future drug target for Alzheimer's disease.Expert opinion on drug discoveryArticle
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.