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Compound class: Synthetic organic
Comment: Semagacestat is a small-molecule γ-secretase inhibitor that was developed by Eli Lilly as a potential treatment for Alzheimer's disease but it failed in Phase 3 clinical trials. NOTCH is also a γ-secretase substrate , and on-target inhibition of NOTCH receptor-related signalling by semagacestat treatment is proposed to be (at least in part) responsible for the unacceptable side effects that were noted in clinical trials, and which lead to termination of the trials .
Ligand Activity Visualisation Charts
These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.✖
1. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG et al.. (2013)
A phase 3 trial of semagacestat for treatment of Alzheimer's disease.
N Engl J Med, 369 (4): 341-50. [PMID:23883379]
2. Kreft AF, Martone R, Porte A. (2009)
Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer's disease.
J Med Chem, 52 (20): 6169-88. [PMID:19694467]
3. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA. (2000)
Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1.
Nat Cell Biol, 2 (7): 463-5. [PMID:10878814]