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Risk-takers at Vanderbilt drive drug discovery research
NASHVILLE, Tenn.—Drug discovery research is frequently criticized for taking the well-traveled path—whether it's the penchant of the U.S. National Institutes of Health (NIH) to fund conservatively couched grant applications or Big Pharma filing yet another New Drug Application for a "me-too-but-a-little-better" therapeutic. The Vanderbilt Center for Neuroscience Drug Discovery (VCNDD), however, is doing it differently.
"When we initiate a program," says the center's director, Dr. P. Jeffrey Conn, "everything we do is focused on high-risk endeavors that are not widely accepted by the pharmaceutical industry. In each case, we build data sets and compounds to de-risk and build interest in a field that ultimately gains the interest of pharma. This includes the companies that we partner with, as well as multiple other companies that initiate programs based on data that we publish and present to validate these new efforts."
Vanderbilt University (VU) Medical Center has been a leader in drug discovery for more than 85 years, and was an early pioneer of the cross-disciplinary translational approach to medical research. The Vanderbilt Program in Drug Discovery was created as a hybrid between academia and pharmaceutical development, combining the high-throughput screening strategies of industry with the in-depth knowledge of basic biological research. The success of this strategy, particularly for the study of neurological disorders, led to the creation of a dedicated VCNDD in early 2011.
The VCNDD is focused on accelerating research that may lead to new treatments for Parkinson's disease, Alzheimer's disease, schizophrenia and other disorders of the brain, combining pharmacology, molecular pharmacology, medicinal chemistry, drug metabolism and pharmacokinetics as part of a multidisciplinary team. This setup broadly mimics the preclinical drug discovery structure found in the pharmaceutical industry, but with greater freedom to explore the higher-risk therapeutic targets commonly associated with neurological disorders.
"A key aspect of successful preclinical discovery programs pursuing drugs for central nervous system (CNS) targets is the efficient and accurate identification of compounds that exhibit favorable blood-brain barrier (BBB) permeation with little or no efflux transporter liabilities, and whose unbound concentrations in the brain freely and rapidly equilibrate with those in plasma," states Dr. Thomas Bridges, a drug discovery scientist in drug metabolism and pharmacokinetics (DMPK) within the VCNDD and the Department of Pharmacology at the VU Medical School. "To that end, our approach provides quantitative insight to compounds' brain distribution properties as a single, largely species-independent variable useful for establishing structure-activity relationships (SAR), medicinal chemical optimization strategies and ultimately, to aid clinical candidate selection."
The throughput and data security advantages offered by automated liquid handling are vital to the VCNDD's ADME screening workflow, and the center uses a Tecan Freedom EVO 200 to provide routine processing of three ADME assays—an intrinsic clearance assay, a plasma protein binding assay using RED (rapid equilibrium dialysis) plates and a cocktail-style cytochrome P450 IC50 assay.
Dr. J. Scott Daniels, assistant professor of pharmacology and director of DMPK at VCNDD, explains: "When I arrived at Vanderbilt, I saw a group of well-meaning, hard-working drug metabolism scientists struggling with limited resources. The pipetting systems we had in place weren't capable of the throughputs and experimental integrity we needed, so we invested in a contemporary liquid-handling platform which met the requirements of our workflow."
With throughput a key consideration, the VCNDD's Tecan unit is equipped with three independent robotic arms—an eight-channel pipetting arm, a 96-channel pipetting arm and a robotic gripper arm—allowing parallel processing of all three assays. Complete automation of these fundamental assays is vital to streamline the DMPK group's workflow, requiring integration of a number of additional devices onto the deck of the instrument. These include incubators, incubated shakers and a microplate reader, providing high-throughput, walkaway processing.
"The Freedom EVO 200 is a workhorse for this type of work, and some labs will be running 100-plus 96-well plates per day through the system with very little, if any, human intervention once the assay is set up," notes Kevin Moore, head of applications and solutions at Tecan. "The unit will easily run up to 500 samples per day in the three assays Vanderbilt is most interested in. Often the system is set up during the day and then run from the afternoon into the evening unattended. Most customers like to run their system daily to ensure a good return on investment. As an example, the setting up of an IC50 plate with compounds at different concentrations using the eight-channel pipetting arm would take around 10 to 15 minutes per plate."
Daniels summarizes: "From struggling with single pipettors on the bench, we have progressed to a fully automated linear platform with which we can perform several bread-and-butter assays every single week, driving the drug discovery pipeline and taking risks in novel targets in a way that companies just cannot do given the current economic climate. By partnering with an experienced laboratory automation equipment manufacturer, we have been able to make our facility into an efficient, high-throughput contemporary ADME group."
What progress has the VCNDD group reported to date? "To date, we have not had any drug candidates in clinical trials," Conn admits. "However, we have reached the stage of achieving preclinical candidate status for three programs, each of which has been partnered with a major company for further development. While we cannot make firm predictions, if we are successful in the preclinical development stage for these efforts, we could be ready to enter into Phase I clinical studies by the end of 2014.