2012 Grants - Li

The Mechanisms of Action of Gamma-Secretase Modulators

Yueming Li, Ph.D.
Sloan-Kettering Institute for Cancer Research
New York, New York

2012 Investigator-Initiated Research Grant

Gamma-secretase is an enzyme that plays a key role in Alzheimer's disease. It is part of the biochemical pathway that produces beta-amyloid, a protein fragment that aggregates into amyloid plaques, one of the hallmarks of Alzheimer's disease in the brain. Several drugs have been tested that block gamma-secretase, but they have many side effects because gamma-secretase also modifies other important proteins, including a family of proteins called the Notch family.

Yueming Li, Ph.D., and colleagues have proposed to study how two classes of drugs modulate the activity of gamma-secretase without affecting Notch processing. They will use sophisticated molecular techniques to determine how these drugs bind to gamma-secretase and change its shape. Dr. Li's team will also study how combinations of gamma-secretase modulators can alter the production of different forms of beta-amyloid. These studies will provide valuable insights into the development of better gamma-secretase inhibitors, which could become drug candidates for the treatment of Alzheimer's disease.