ArticleJournal of medicinal chemistry2021
Structural Insights into Notum Covalent Inhibition.
Article in Journal of medicinal chemistry, 2021. 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 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.
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Who cites it
10 citing papers in PubMed.
- Discovery of anthraquinones as potent Notum inhibitors for treating osteoporosis by integrating biochemical, phytochemical, computational, and experimental assays.Journal of pharmaceutical analysis · 2026Article
- High-efficient discovering the potent anti-Notum agents from herbal medicines for combating glucocorticoid-induced osteoporosis.Acta pharmaceutica Sinica. B · 2025Article
- Comprehensive investigation of multiple targets in the development of newer drugs for the Alzheimer's disease.Acta pharmaceutica Sinica. B · 2025Review
- Article
- Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity.European journal of medicinal chemistry · 2023Article
- HyperCys: A Structure- and Sequence-Based Predictor of Hyper-Reactive Druggable Cysteines.International journal of molecular sciences · 2023Article
- Structural Analysis and Development of Notum Fragment Screening Hits.ACS chemical neuroscience · 2022Article
- Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit.Journal of medicinal chemistry · 2022Article
- Article
- Proteome-Wide Profiling of the Covalent-Druggable Cysteines with a Structure-Based Deep Graph Learning Network.Research (Washington, D.C.) · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors.
Funding
Abstract
The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer's disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors.
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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.