Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases

Notch is a membrane inserted protein activated by the membrane-inserted gamma-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the gamma-secretase inhibitor-based prodrugs 13a and 15a as substrates for gamma-glutamyltranspeptidase (gamma-CT) and/or gamma-glutamylcy-dotransferase (gamma-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-gamma-Glu-gamma-secretase inhibitor prodrug 13a (gamma-GT-targeting and gamma-GCT-targeting) but not from Ac-alpha-Glu-gamma-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the gamma-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notchl could be selectively down-regulated upon treatment with the Ac-gamma-Glu-gamma-secretase-inhibitor 13a.