AB AND BEYOND: Y-SECRETASE A DRUG TARGET FOR CNS DISEASE Funded Grant uri icon

description

  • Data generated by the investigators in this program project grant and others indicate that gamma-secretase inhibitors (GSIs) may be useful drugs in such diverse settings Alzheimer's Disease (AD), cancer, multiple sclerosis, and immune rejection, and that the adverse effects caused by GSIs are not insurmountable. We will use GSIs as tools to explore the therapeutic potential of targeting gamma-secretase in vivo. In the context of this program project the main goal of the chemistry core will be to synthesize sufficient GSI to support the studies in Projects 1-3 and develop methods to measure GSI levels in body fluids and tissues following in vivo dosing. The aims of the Chemistry Core are: Aim 1. To synthesize all four L-alanine-containing enatiomerically pure diastereomers of LY-411,575, an extremely potent gamma-secretase inhibitor (GSI), and to isolate large quantities of the most potent diastereomer of LY-411,575 for in vivo studies. Aim 2. To develop a reliable method of qualitative and quantitative analysis of LY-411,575 stereoisomers and related analytes and metabolites in biological fluids and tissues. Aim 3. To synthesize other GSIs required for the studies proposed in projects 1-3.
  • Gamma-Secretase is a protease that catalyzes intramembrane cleavage of an expanding list of substrates. One of the actions of gamma-secretase is to cleave Abeta from its precursor (APP). As Abeta accumulation is thought to play a causal role in the development of Alzheimer's Disease (AD) and gamma-secretase inhibitors block Abeta production, gamma-secretase has come under intense scrutiny as a potential target for AD therapeutics. As a result, highly potent inhibitors of gamma-secretase with excellent in vivo pharmacologic properties have been developed as potential therapeutic agents for AD. It is believed that such inhibitors will lower Abeta in vivo, prevent its accumulation, and may have beneficial effect on AD. However, it is also believed that the utility of gamma-secretase inhibitors will be limited due to inhibition of gamma-secretase regulated signaling events mediated by other substrates, especially signaling events mediated by Notch. Our preliminary data indicates that these gamma- secretase inhibitors may have therapeutic utility in such diverse settings as AD, cancer, multiple sclerosis, and immune rejection. Thus, the overall thrust of this program project is to utilize an orally bioavailable gamma-secretase inhibitor to rigorously evaluate its therapeutic potential. More specifically, we hypothesize that in certain conditions inhibition of APP processing, Notch signaling, and other physiologic effects of a gamma-secretase inhibitor will have beneficial effects that outweigh potential toxicities. hi this project we will 1) develop biomarker assays that will enable us to evaluate the extent of Notch inhibition in vivo, 2) use gamma-secretase inhibitors to explore the relationship between extent of Abeta reduction in vivo and alteration in Abeta deposition 3) obtain information on dosing, degree of inhibition of APP and Notch, and toxicity vital to the other projects and 4) explore the role of Notch singling and the effect of gamma-secretase mediated inhibition of that signaling in a mouse model of toxin induced demyelination and experimental autoimmune encephalitis.