γ-Secretase is a protease complex that cleaves single-pass transmembrane proteins, such as Notch receptors and β-amyloid precursor protein (APP), within the transmembrane domain. Semagacestat is a potent inhibitor of γ-secretase that blocks the production of Aβ38, Aβ40, and Aβ42 with IC50 values of 12.0, 12.1, and 10.9 nM, respectively. It also blocks Notch signaling (IC50 = 14.1 nM). Semagacestat modulates γ-secretase activity in vivo, altering Aβ levels in brain, cerebrospinal fluids, and plasma in a dose-dependent fashion. Although semagacestat does not improve cognitive status in humans, it is useful as a pan γ-secretase inhibitor for research purposes.
