Development of Small Molecule Inhibitors of Tau Oligomerization

Pipeline Grant

Principal Investigator: Dr. Joseph B. Rayman, Assistant Professor of Medical Sciences at Columbia University Irving Medical Center

Progressive supranuclear palsy (PSP) and other tauopathies are characterized by pathological accumulation of tau protein in vulnerable areas of the brain. Abnormal tau may interfere with normal brain function and promote neurodegeneration, and is therefore considered a potential therapeutic target. Of the many complex structural variations of tau protein, recent evidence suggests that the oligomeric form of tau is especially pathogenic. However, there are no approved drugs that effectively target oligomeric tau.

Our research team has designed compounds that block the production of oligomeric tau in mouse models of neurodegenerative disease. Importantly, compounds that limit accumulation of oligomeric tau in the mouse brain prevent neuronal loss and ameliorate cognitive and motor deficits. While these results are encouraging, they are based on a very limited set of active compounds. To maximize the likelihood of developing effective therapeutics for humans, it is critical to expand the series of chemical structures that has shown therapeutic potential thus far. Using well-validated and robust screening technologies that we established previously, we will identify new compounds that prevent oligomerization of tau, and from these develop additional therapeutic candidates for advanced preclinical testing and possibly clinical trials in humans.

The lack of disease-modifying drugs for PSP magnifies that need to explore novel and innovative therapeutic approaches. By expanding the scope of our existing chemistry efforts in the development of first-in-class tau agents, we are in a stronger position to translate our discoveries into safe and effective therapeutics for PSP and other tauopathies with critical unmet medical need.