Gamma-Secretase Modulators for Alzheimer's Disease

All of the specific aims in this research address one main goal: to identify gamma-secretase modulating drugs that are efficacious in a standard Alzheimer’s disease transgenic animal model and suitable for pre-clinical drug development. The ultimate goal is to identify a drug candidate for the treatment of Alzheimer’s disease.

The goal of this project is to identify new agents that lower brain levels of amyloid, a protein widely thought to initiate Alzheimer’s disease. We seek to accomplish this by selectively affecting an amyloid-producing enzyme so that this enzyme can continue serving a critical role it plays in normal human health. We have identified small, drug-like molecules that affect the enzyme in this way and now seek to advance them by (1) making variations of these molecules to optimize their selective effects on the amyloid-producing enzyme; (2) evaluating promising molecules for other properties that would suggest they might last long enough in the body be able to get where they need to be; (3) testing drug candidates in animal models for Alzheimer’s disease; and (4) working toward the identification of backup drug candidates.

Progress Updates

Dr. Wolfe’s Laboratory for Experimental Alzheimer Drugs (LEAD) has been focused on searching for promising drugs that block the ability of an enzyme called ‘gamma-secretase’ from producing the amyloid beta-protein (or A-beta)—a protein strongly linked to Alzheimer’s disease (AD). Gamma-secretase has a critical normal function in the human body and any potential drug needs to effectively block A-beta production while leaving this required normal function intact. LEAD has identified new candidates that have both of these characteristics. In addition, some of the candidates possess other important advantages (such as small size, good solubility, and potentially improved brain entry) over drugs that have been or are now in human trials. The focus during Year 2 of the program has been to identify new candidates that have better drug-like profiles than the most promising candidates from Year 1. During Year 2, LEAD has designed, synthesized and tested almost 150 variations of its promising class of candidates, several of which show more than 150-fold increases in activity and have improved drug-like profiles that make them suitable for testing in animals with AD-like traits. This has set a new benchmark for Year 3, as these new compounds may exhibit more effectiveness in animals than did the most promising candidate identified in Year 1. That candidate was able to lower A-beta levels in the brain in an AD mouse without any apparent toxic effects.