Semagacestat (LY450139) is a -secretase blocker for A42, A40 and A38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM.
Semagacestat reduces the secretion of A42, A40 and A38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium, with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively, without affecting cell viability. Semagacestat also increases -CTF in cell lysates with ECmax of 16.0 nM, and the increase can be unexpectedly attenuated at high concentrations. Semagacestat inhibits Notch signaling with IC50 of 14.1 nM, and shows minimal Notch-sparing selectivity with Notch IC50/A42 IC50 only 1.3 . Semagacestat causes a concentration-dependent decrease in A40 secreted into the medium with IC50 of 111 nM from murine CTX expressing endogenous murine APP, but murine A42 formation in CTX is roughly 12-fold less than A40 in accordance with data for neurons from wild type mice