ArticleNature2008
Substrate-targeting gamma-secretase modulators.
Article in Nature, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
140 citing papers in PubMed, 277 citations in OpenAlex.
- Trial
- Substrate-Selective Inhibition of the SARS-CoV-2 Papain-Like Protease: Inhibition of Hydrolysis of Human Over Viral Substrates.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- Aducanumab delivery via focused ultrasound-induced transient blood-brain barrier opening in vivo.Scientific reports · 2025Article
- Melatonin Supplementation Alleviates Impaired Spatial Memory by Influencing AβInternational journal of molecular sciences · 2024Article
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- 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
- Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production.International journal of molecular sciences · 2023Article
- Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease.Frontiers in molecular neuroscience · 2023Review
- Sulindac sulfide as a non-immune suppressive γ-secretase modulator to target triple-negative breast cancer.Frontiers in immunology · 2023Article
- Notch signaling pathway: architecture, disease, and therapeutics.Signal transduction and targeted therapy · 2022Review
- Microglia in Alzheimer's Disease: a Key Player in the Transition Between Homeostasis and Pathogenesis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
- Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue.Molecules (Basel, Switzerland) · 2021Article
- Targeting Notch in oncology: the path forward.Nature reviews. Drug discovery · 2021Review
- Article
- Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations.Acta neuropathologica communications · 2020Article
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- The Use of Antimicrobial and Antiviral Drugs in Alzheimer's Disease.International journal of molecular sciences · 2020Review
- Substrate interaction inhibits γ-secretase production of amyloid-β peptides.Chemical communications (Cambridge, England) · 2020Article
- Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation.EMBO reports · 2020Article
- Targeting Amyloidogenic Processing of APP in Alzheimer's Disease.Frontiers in molecular neuroscience · 2020Review
80 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
29 authors at 8 institutions in 4 countries.
Funding
Abstract
Selective lowering of Abeta42 levels (the 42-residue isoform of the amyloid-beta peptide) with small-molecule gamma-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the gamma-secretase complex, but instead labelled the beta-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-beta peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP gamma-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-beta act as GSMs, and some GSMs alter the production of cell-derived amyloid-beta oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Abeta42 production and inhibition of amyloid-beta aggregation, which may synergistically reduce amyloid-beta deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets.
Indexed as
Identifiers
What OpenQuestion holds
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.