"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.

Gaps in Alzheimer's Biology

One major obstacle to developing better therapies is that researchers still do not fully understand the biology behind Alzheimer's disease. The same problem affects research into many other neurological diseases and neurodevelopmental disorders.

Scientists have identified genes and proteins that may contribute to these conditions, but studying them can be extremely difficult when researchers lack a reliable way to change how those biological targets behave.

One approach involves using tool compounds. These chemicals interact with particular proteins and either raise or reduce their activity. Although many tool compounds are unsuitable for use as medicines because they may affect unintended targets or cause toxicity, they are still highly valuable for investigating what a protein does. That knowledge can become an important early step toward developing new treatments.

Targeting the TAOK1 Protein

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 TAOK-1. The protein has been linked to Alzheimer's disease, but it has remained poorly understood partly because researchers have lacked suitable compounds for studying it.

Most of the work was carried out at the WCNDD under the leadership of Executive Director Craig Lindsley. The WCNDD is a clinical-stage biotech start-up within Vanderbilt. Its drug discovery pipeline currently includes five compounds in phase I clinical trials.

The center 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.

To find useful compounds, Schultz, Parr, and other WCNDD researchers created a large collection of related molecules. Each one had a slightly different structure. The team then evaluated how the compounds affected TAOK-1 and assessed whether they had properties considered desirable in potential drugs.

"This project showcased the strength of the WCNDD's drug discovery infrastructure," Schultz said.

The First Selective TAOK1 Inhibitor

The collaboration led to the discovery of VU6083859, the first selective inhibitor of TAOK-1. The compound could provide a starting point for research aimed at developing future Alzheimer's disease treatments.

Another molecule produced an unexpected result. The compound, named VU6080195, activated all three proteins in the TAOK family rather than inhibiting them.

"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 the two compounds will encourage more researchers to investigate the TAOK protein family. So far, these proteins have received relatively little attention in in vivo models.

New Tools for Alzheimer's Research

A deeper understanding of disease biology can improve the chances of finding effective treatments. With these two compounds now available, neuroscientists can examine how the TAOK protein family functions and explore its links to Alzheimer's and other neurological diseases.

The findings could eventually help researchers identify new treatment strategies and perhaps contribute to the long-term search for a cure.

The paper "Discovery of VU6083859, a TAOK1 Selective Inhibitor, and VU6080195, a pan-TAOK Activator" was published in ACS Chemical Neuroscience.

The research used funding from the William K. Warren Foundation and received support from 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.