[³H]‐L685,458 Binding Sites are Abundant in Multiple Peripheral Organs in Rats: Implications for Safety Assessment of Putative γ‐Secretase Targeting Drugs

Abstract

c-Secretase is a multimeric enzyme complex that carries out proteolytic processing to a variety of cellular proteins. It is currently explored as a therapeutic target for Alzheimer's disease (AD) and cancer. Mechanism-based toxicity needs to be thoroughly evaluated for c-secretase inhibitory and/or modulatory drugs. This study comparatively assessed putative c-secretase catalytic sites in rat peripheral tissues relative to brain and explored an effort of its pharmacological inhibition on hair regeneration. Using [ 3 H]-labelled L685,458, a potent c-secretase inhibitor, as probe, we found more abundant presence of c-secretase binding sites in the liver, gastrointestinal tract, hair follicle, pituitary gland, ovary and testis, as compared to the brain. Local application of L658,458 delayed vibrissal regrowth following whisker removal. These results suggest that c-secretase may execute important biological functions in many peripheral systems, as in the brain. The development of c-secretase inhibitors/modulators for AD and cancer therapy should include close monitoring of toxicological panels for hepatic, gastrointestinal, endocrinal and reproductive functions.

Quantitative comparison of presenilin protein expression reveals greater activity of PS2‐γ‐secretase

“…5 Consequently, γsecretase has been proposed as a therapeutic target, with the development of inhibitors of PS-related γsecretase activity. [6][7][8][9][10] However, these molecules have failed in clinical trials due to off-target effects, which are thought to be caused by the inhibition of substrates other than APP, particularly Notch1, 7,11,12 and may be influenced by differences in affinity for PS1-and PS2-γsecretase. [13][14][15] More recently, the focus has shifted to the development of γsecretase modulators (GSMs), small molecules that modulate the type of Aβ peptides released, while still maintaining cleavage of the intracellular domain of substrates.…”

Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators

“…Many first generation GSIs, including L-685,458, were peptidic transition state analogs that feature hydroxyethylene dipeptide isostere moieties, allowing them to bind to γ-secretase in a way that mimics the α-helical nature of the APP TM domain [ 18 ]. However, these molecules lack Notch-sparing activity and thus have not been pursued for development as therapeutic agents [ 19 ]. The identification of a region on the γ-secretase surface which is responsible for initial substrate binding [ 20 ] led to a focus on identifying GSIs that target the substrate-docking site of the enzyme.…”