ArticleNature communications2016
Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors.
Article in Nature communications, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
What it found
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Who cites it
34 citing papers in PubMed, 76 citations in OpenAlex.
- The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.EMBO molecular medicine · 2018Trial
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- The state of the art in secondary pharmacology and its impact on the safety of new medicines.Nature reviews. Drug discovery · 2024Review
- Chemoproteomics, A Broad Avenue to Target Deconvolution.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Review
- Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception.Molecular and cellular neurosciences · 2023Article
- The evolving role of investigative toxicology in the pharmaceutical industry.Nature reviews. Drug discovery · 2023Review
- Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome.iScience · 2022Article
- Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment ofJournal of medicinal chemistry · 2022Article
- The emerging role of mass spectrometry-based proteomics in drug discovery.Nature reviews. Drug discovery · 2022Review
- Small molecule photocatalysis enables drug target identification via energy transfer.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Finding New Ways How to Control BACE1.The Journal of membrane biology · 2022Article
- Organocatalytic atroposelective construction of axially chiral N, N- and N, S-1,2-azoles through novel ring formation approach.Nature communications · 2022Article
- Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.Journal of Alzheimer's disease reports · 2022Article
- The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.Nature reviews. Neurology · 2021Review
- Photoaffinity labelling strategies for mapping the small molecule-protein interactome.Organic & biomolecular chemistry · 2021Review
- Recent Advances about the Applications of Click Reaction in Chemical Proteomics.Molecules (Basel, Switzerland) · 2021Review
- A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing.Scientific reports · 2021Article
- How Physiologic Targets Can Be Distinguished from Drug-Binding Proteins.Molecular pharmacology · 2021Article
- Formation of Lipofuscin-Like Autofluorescent Granules in the Retinal Pigment Epithelium Requires Lysosome Dysfunction.Investigative ophthalmology & visual science · 2021Article
- A target safety assessment of the potential toxicological risks of targeting plasmepsin IX/X for the treatment of malaria.Toxicology research · 2021Review
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.
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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.