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

Notch
is a membrane inserted protein activated by the membrane-inserted
γ-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 γ-secretase
inhibitor-based prodrugs 13a and 15a as
substrates for γ-glutamyltranspeptidase (γ-GT) and/or
γ-glutamylcyclotransferase (γ-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-γ-Glu-γ-secretase inhibitor
prodrug 13a (γ-GT-targeting and γ-GCT-targeting)
but not from Ac-α-Glu-γ-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to
blood and liver. Potential nephroprotective effects of the γ-secretase
inhibitor targeted prodrugs were investigated in vivo in a mouse model
of acute kidney injury, demonstrating that the expression of Notch1
and cleaved Notch1 could be selectively down-regulated upon treatment
with the Ac-γ-Glu-γ-secretase-inhibitor 13a.