title: Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases.
abstract: 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.
authors.affiliation: Transplantation Center, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL) , CH-1011 Lausanne, Switzerland.|University Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL) , CH-1011 Lausanne, Switzerland.
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , CH-4070 Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Flohr
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , CH-4070 Basel, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , CH-4070 Basel, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Walter
authors.affiliation: Transplantation Center, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL) , CH-1011 Lausanne, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Wyss
authors.affiliation: Transplantation Center, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL) , CH-1011 Lausanne, Switzerland.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Transplantation Center, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL) , CH-1011 Lausanne, Switzerland.
authors.forename: Dela
authors.initials: D
authors.lastname: Golshayan
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , CH-4070 Basel, Switzerland.
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Aebi
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D045744:Cell Line, Tumor; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D012076:Renal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005722:gamma-Glutamylcyclotransferase / Q000037:antagonists & inhibitors
chemical_list: D011355:Prodrugs; D051880:Receptors, Notch; D012076:Renal Agents; D053829:Amyloid Precursor Protein Secretases; D005722:gamma-Glutamylcyclotransferase