Cognitive dysfunctions are common symptoms for Alzheimer's disease, schizophrenia, and other disorders of the central nervous system. Most people are familiar with the memory problems as one type of dysfunction, but cognitive dysfunctions encompass other aspects such as language use, complex attention, and social cognition.
Researchers at the Warren Center for Neuroscience Drug Discovery, a leading academic drug discovery center that features state-of-the-art technology and instrumentation typically only found in major pharmaceutical companies, have been at the forefront of drug discovery efforts to treat serious brain disorders. VU319, a compound designed to improve memory loss in people with Alzheimer's disease, advanced into phase 1 clinical trials in 2020. The results were promising: VU319 demonstrated cognitive improvements with no side effects.
To expand upon their previous work, researchers led by Craig Lindsley, University Distinguished Professor of Biochemistry and Pharmacology and executive director of the WCNDD, aimed to develop a backup compound for VU319 that might show additional therapeutic potential. Their work was published in ACS Chemical Neuroscience in August 2024 and was one of the top-20 most downloaded articles that month.
The backup candidate compound, VU6007496, is a positive allosteric modulator-a PAM-for a neurotransmitter receptor called M1 muscarinic acetylcholine receptors. PAMs selectively bind to a particular part of a receptor in a way that they can modulate the receptor's activity. Neurons that produce the neurotransmitter acetylcholine fail in the beginning stages of Alzheimer's disease, but using PAMs to increase the sensitivity of M1 receptors in still-healthy neurons could combat memory loss.
We sat down with Julie Engers, research assistant professor of pharmacology and lead researcher on the ACS Chemical Neuroscience paper, to learn about the WCNDD's most recent work.
What was unique about your approach to the research? Was anything about the work unique to Vanderbilt University?
The M1 PAM program is deemed too risky by most of the pharmaceutical industry. This was an opportunity for the WCNDD to develop VU319 because of its unique structure and mode of action. At the WCNDD, we operate like a biotech company within an academic setting, which gives us advantages in developing drugs that might take longer or have dependencies that the market cannot withstand. VU319 advanced into phase 1 single ascending dose clinical trials, was well tolerated with no side effects, and demonstrated cognitive improvement. With these promising results, a chemical back-up program was initiated, and this is the focus of the publication.
What were your findings?
In the lead optimization campaign, we identified VU6007496. Unanticipated findings, including species-specific metabolism, in vitro/in vivo disconnects, and active metabolites that were toxic, affected VU6007496's status as a successful compound candidate. We did find, however, that although VU6007496 had adverse side effects in mice, no such side effects were observed in rats, which makes VU6007496 useful for studying selective M1 activation in vivo.
What do you hope will be achieved with these published results?
Ultimately, we hope our research contributes to improving the lives of people with CNS disorders and their loved ones.
The unexpected findings around VU6007496 provide information that will guide future chemical series and aid in the progression of our M1 PAM program. This information showcases the importance of extensive safety profiling in drug discovery-profiling of all metabolites and their potential to be toxic. The publication of our work will also inform pharmaceutical companies and researchers in this field about the complexities of drug discovery.
Who or what made the difference in your research? What small things contributed to your work?
I am greatly honored to work with many incredibly talented chemists and pharmacologists. This work was a collaborative effort between everyone from the Lindsley lab and all WCNDD Discovery Teams: medicinal chemistry (led by Lindsley and Darren Engers), molecular pharmacology (led by Colleen Niswender and Hyekyung Plumley), drug metabolism and pharmacokinetics (led by Olivier Boutaud and Annie Blobaum), and behavioral pharmacology (led by Carrie Jones and Jerri Rook). Characterization of the lead compound, VU6007496, by our amazing DMPK team provided important details on metabolite identification, species-specific metabolism, and the potential for undesired adverse events.
Finally, this work would not have been possible without the generous endowment from William K. Warren, Jr., and the William K. Warren Foundation. We are immensely grateful for their continued support.
Where is this research taking you next?
With Acadia Pharmaceuticals we will continue our shared pursuit of finding M1 PAM compounds that will improve an individual's cognitive dysfunction with minimal undesired side effects.
Go deeper
The paper "Discovery of VU6007496: Challenges in the Development of an M1 Positive Allosteric Modulator Backup Candidate" was published in ACS Chemical Neuroscience in August 2024.
Funding
This research used funds from the National Institutes of Health, Acadia Pharmaceuticals, and the William K. Warren Foundation.
Shared resources
This research made use of the Laboratory for Neurobehavior.
