Not all gamma secretase inhibitors are created equal
Right. Lilly's 1st generation semagacestat did not distinguish well between APP and Notch (and who knows how many other substrates). Bristol's avagacestat suppose to be more active for APP processing vs. notch cleavage and so to have a better therapeutic index than semagacestat. However, data from phase II suggest its selectivity is not good enough i.e. margin between lowering Aß42 and affecting Notch is too small. Pfizer's compound begacestat is also a 2nd generation Notch sparing (relatively) gamma secretase inhibitor but never heard about it after phase I and my guess they have discontinued development for the very same reason.
The gamma secretase activator data reported in the elegant work of the Greengard group (thanks for posting!), is exciting and could be a potential therapeutic path for AD (perhaps via some regulator of the activator), and I'm hoping to see it replicated and pursued as a target in the clinic.
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