Compound E

• Cell-permeable, potent, and non-competitive selective inhibitor of γ-secretase and Notch pathway
• Inducer of neuronal differentiation
• Active in vitro and in vivo

γ-Secretase is a multimeric and transmembrane aspartyl protease constituted of four subunits: presenilin, nicastrin, Aph-1, and Pen-2. Presenilin is the catalytic subunit of γ-secretase. The carboxyl-terminal fragments (CTFs) of Amyloid precursor protein (APP) and of Notch are two well-known substrates of γ-secretase. Aberrant cleavage of these substrates by γ-secretase is associated with Alzheimer’s disease and cancer, respectively. g-Secretase is, therefore, a promising drug target. Compound E is a cell permeable, potent, selective, and non-competitive inhibitor of γ-secretase. It inhibits the cleavage of both APP and Notch CTFs (IC₅₀=0.3nM for total β-amyloid). At higher concentrations (20-400µM), It only weakly affects the activity of presenilin. Compound E was shown to impede ovarian folliculogenesis, promotes neuronal differentiation, and down-regulate thymocyte development.