Alzheimer’s disease is the leading cause of dementia and affects more than seven million people in the United States. While some treatments can slow disease progression, most available therapies focus on managing symptoms, and there is currently no cure or preventive treatment.
“Alzheimer’s disease remains a major challenge for researchers seeking to develop effective treatments and preventive therapies,” said Daniel Schultz, a former postdoctoral fellow at the Vanderbilt University Warren Center for Neuroscience Drug Discovery.
Understanding the Biology of Alzheimer’s Disease
One of the biggest challenges in developing new Alzheimer’s treatments is that scientists still do not fully understand the biological mechanisms that drive the disease. Similar challenges affect research into other neurological diseases and neurodevelopmental disorders.
Researchers have identified genes and proteins that may contribute to these conditions. However, studying their roles can be difficult without reliable tools to increase or decrease the activity of specific biological targets.
Scientists often use tool compounds to investigate these targets. These chemical compounds interact with specific proteins and can either increase or reduce their activity. Although many tool compounds are not suitable for use as medicines because they may affect unintended targets or cause toxicity, they are valuable research tools. Understanding how a protein functions can provide an important first step toward developing new treatments.
Researchers Identify TAOK1 as a Potential Alzheimer’s Target
In a study published in ACS Chemical Neuroscience, Schultz and co-first author Lauren Parr, a Ph.D. student in the Department of Pharmacology, developed a compound that selectively inhibits TAOK1. The protein has been associated with Alzheimer’s disease, but its role has remained poorly understood partly because researchers have lacked effective compounds for studying it.
Most of the research was conducted at the Warren Center for Neuroscience Drug Discovery, or WCNDD, under the direction of Executive Director Craig Lindsley. The WCNDD is a clinical-stage biotechnology start-up within Vanderbilt University, with a drug discovery pipeline that includes five compounds in Phase I clinical trials.
The center is also a founding pillar of the Vanderbilt Institute for Therapeutic Advances, a next-generation drug discovery institute also led by Lindsley.
To identify promising compounds, Schultz, Parr, and their WCNDD colleagues created a large library of related molecules with slightly different chemical structures. The researchers then tested how each compound affected TAOK1 and evaluated whether the molecules had characteristics desirable in potential drug candidates.
“This project demonstrated the strength of the WCNDD’s drug discovery infrastructure,” Schultz said.
Discovery of the First Selective TAOK1 Inhibitor
The research led to the discovery of VU6083859, the first selective TAOK1 inhibitor. This compound may serve as an important research tool and a starting point for future studies aimed at developing new Alzheimer’s disease treatments.
The researchers also identified another molecule with an unexpected effect. Known as VU6080195, the compound activated all three proteins in the TAOK family rather than inhibiting them.
“Our understanding of TAOK proteins has largely focused on their inhibition, so we are excited about the opportunity to study the neurological effects of increasing their activity,” Schultz said. “Scientists can become focused on detailed plans and expected outcomes, so it was exciting to see this unexpected result.”
Schultz hopes the two compounds will encourage additional research into the TAOK protein family. To date, these proteins have received relatively little attention in in vivo models.
New Research Tools for Alzheimer’s Disease
A better understanding of Alzheimer’s disease biology could improve the chances of developing effective therapies. With these two compounds now available, neuroscientists can study how the TAOK protein family functions and investigate its potential connections to Alzheimer’s and other neurological diseases.
The findings may eventually help researchers identify new treatment strategies and contribute to the long-term effort to develop a cure for Alzheimer’s disease.
The study, titled “Discovery of VU6083859, a TAOK1 Selective Inhibitor, and VU6080195, a pan-TAOK Activator,” was published in ACS Chemical Neuroscience.
The research was funded by the William K. Warren Foundation and supported by the Zenobia and Mark Godschalk Alzheimer’s Research Endowment, the Helen H. and Morris D. Hartman, MD 1910, Neurological Research Fund, the Warren Center for Neuroscience Drug Discovery, and the Vanderbilt Institute for Therapeutic Advances.
Source: www.sciencedaily.com