Alzheimer’s disease is the most common cause of dementia, and it affects over seven million people in the United States alone. Although there are treatments that can slow its progression, most of them treat its symptoms only and none of them can cure the disease.
“Alzheimer’s is a condition that remains recalcitrant to the scientific community’s attempts at developing a cure or preventative treatment,” said Daniel Schultz, a former postdoctoral fellow in the Vanderbilt University Warren Center for Neuroscience Drug Discovery.
A critical contributor to this significant, unmet need for therapeutics—not just for Alzheimer’s, but for a wide array of neurological diseases and neurodevelopmental disorders—is the fact that there are still quite a few gaps in our understanding of their underlying biology. Although we know about specific genes and proteins that may play roles in different neurological conditions, it can be difficult, if not impossible, to study them if scientists can’t figure out how to modulate their function.
One way in which researchers can affect the activity of a protein is by targeting it with tool compounds. Tool compounds are simply compounds that interact with a specific protein to increase or decrease its activity. Many are not good drug candidates because they can have off-target effects and toxicities, but they can still be indispensable tools for probing the function of a protein of interest—a key step in the development of potential treatments.
In a recent paper published in ACS Chemical Neuroscience, co-first authors Schultz and Lauren Parr, a Ph.D. student in the Department of Pharmacology, developed a tool compound that selectively inhibits TAOK-1, which is linked to Alzheimer’s but which has not been thoroughly studied due, in part, to a lack of tool compounds to study it with.
The work was primarily conducted within the WCNDD and was led by WCNDD Executive Director Craig Lindsley. The WCNDD is a clinical-stage biotech start-up within Vanderbilt with a drug discovery pipeline that currently has five compounds in phase I clinical trials. The WCNDD is also a founding pillar of the new Vanderbilt Institute for Therapeutic Advances, a next-generation drug discovery institute that is also led by Lindsley.
For the recent study, Schultz, Parr, and the team of WCNDD researchers synthesized a large library of compounds, each slightly different than the rest, and tested their TAOK-1 activity and drug-like properties.
“This project showcased the strength of the WCNDD’s drug discovery infrastructure,” Schultz said. The seamless teamwork resulted in the discovery of the first selective inhibitor of TAOK-1, a compound that the researchers dubbed VU6083859 and that may serve as the starting point for future Alzheimer’s disease treatments.
A single other compound stood out from among the rest: VU6080195, which the team determined acts as an activator of all three proteins in the TAOK family—a serendipitous result.
“Our understanding of TAOK proteins largely centers around their inhibition, so we are excited at the prospect of studying the neurological effects of increasing their activity,” Schultz said. “As scientists, we can get lost in planning our projects to the last detail and expecting things to go a certain way, so it was quite fun to see this unexpected result.”
Schultz hopes that the two new tool compounds will spur renewed interest in studying the TAOK family, which has seen very little study in in vivo models.
The better our understanding of the underlying biology of diseases, the better our chances are of treating them. With two new tool compounds available, neuroscientists can get to work on probing a protein family with ties to Alzheimer’s and other neurological diseases, perhaps laying the groundwork for new treatments, or perhaps even a cure.
Go deeper
The paper “Discovery of VU6083859, a TAOK1 Selective Inhibitor, and VU6080195, a pan-TAOK Activator” was published in ACS Chemical Neuroscience in January 2026.
Funding
This research used funds from the William K. Warren Foundation and was 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.