ArticleNature structural & molecular biology2025
Structural basis of human γ-secretase inhibition by anticancer clinical compounds.
Article in Nature structural & molecular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Role of epithelial-mesenchymal transition (EMT) in malignancies: current status and future prospects.Signal transduction and targeted therapy · 2026Review
- Neuroinflammation and Secretase Regulation in Alzheimer's Disease: From Molecular Cross-Talk to Multi-Target Therapeutics.International journal of molecular sciences · 2026Review
- Notch signaling in the tumor microenvironment: recent advances and targeted therapeutics.Molecular cancer · 2026Review
- Alzheimer's Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective.International journal of molecular sciences · 2025Review
- Nuclear MicroRNA-124-3p Promotes Neurite Outgrowth After Spinal Cord Injury by Enhancing Cttn Transcription.Molecular neurobiology · 2025Article
- The role of notch signaling pathway and non-coding RNAs in cancer and inflammation: progress, therapeutic insights, and future directions.Frontiers in immunology · 2025Review
- Notch signaling pathway modulation by food functional ingredients: mechanisms, cancer and immunoregulation.Frontiers in cell and developmental biology · 2025Review
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Authors and funding
10 authors.
Funding
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Abstract
Aberrant activation of Notch signaling, mediated by the Notch intracellular domain (NICD), is linked to certain types of cancer. The NICD is released through γ-secretase-mediated cleavage of the Notch receptor. Therefore, development of a γ-secretase inhibitor (GSI) represents an anticancer strategy. Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. Three of the five GSIs are in active anticancer clinical trials, while nirogacestat was recently approved. Each of these GSIs similarly occupies the substrate-binding site of presenilin 1 but shows characteristic differences in detailed recognition pattern. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency.
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Registered trials
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