Quantitative High-Throughput Screening Yields Potential Alzheimer's Disease Drugs

The search for small molecules to prevent the formation of the tau protein clots that characterize neurodegenerative disorders such as Alzheimer's disease has borne fruit with discovery of a new class of molecules called aminothienopyridazines (ATPZs).

Tau proteins are microtubule-associated proteins that are abundant in neurons in the central nervous system and are less common elsewhere. They interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules.

Phosphorylation of tau is regulated by a host of kinases including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization. Hyperphosphorylation of the tau protein can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease and other "tauopathies”.

To find useful tau inhibitors investigators at the University of Pennsylvania School of Medicine (Philadelphia, USA) and the [U.S.] National Institutes of Health (Bethesda, MD, USA) conducted quantitative high-throughput screening assays of more than 292,000 compounds housed in the National Institutes of Health's Chemical Genomics Center.

Results published in the August 18, 2009, issue of the journal Biochemistry revealed that 285 compounds were of potential interest. Of these, the investigators focused on the ATPZs, since they best fit the criteria for potential drug candidacy such as proper size, desirable chemical properties, specificity for the tau protein, and a predicted likelihood of crossing the blood-brain barrier. Further characterization of representative ATPZ compounds showed they did not interfere with tau-mediated microtubule assembly, and they were significantly more effective at preventing the fibrillization of tau than other drugs tested.

"While we are excited about the discovery of this new series of tau fibril inhibitors, we are still a long ways from turning these early lead compounds into drugs,” cautioned corresponding author Dr. Kurt R. Brunden, professor of neurodegenerative diseases at the University of Pennsylvania School of Medicine. "However, we believe that certain of our ATPZ compounds will be very useful in allowing us to gain a better understanding of the consequences of inhibiting tau fibril formation in transgenic mouse models of Alzheimer's disease.”

Related Links:
University of Pennsylvania School of Medicine
National Institutes of Health