NASHVILLE, Tenn.—Drug discovery research is frequentlycriticized for taking the well-traveled path—whether it's the penchant of theU.S. National Institutes of Health (NIH) to fund conservatively couched grantapplications or Big Pharma filing yet another New Drug Application for a"me-too-but-a-little-better" therapeutic. The Vanderbilt Center for NeuroscienceDrug 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 acceptedby the pharmaceutical industry. In each case, we build data sets and compoundsto de-risk and build interest in a field that ultimately gains the interest ofpharma. This includes the companies that we partner with, as well as multipleother companies that initiate programs based on data that we publish andpresent to validate these new efforts."
Vanderbilt University (VU) Medical Center has been a leaderin drug discovery for more than 85 years, and was an early pioneer of thecross-disciplinary translational approach to medical research. The VanderbiltProgram in Drug Discovery was created as a hybrid between academia andpharmaceutical development, combining the high-throughput screening strategiesof industry with the in-depth knowledge of basic biological research. Thesuccess 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 leadto new treatments for Parkinson's disease, Alzheimer's disease, schizophreniaand other disorders of the brain, combining pharmacology, molecularpharmacology, medicinal chemistry, drug metabolism and pharmacokinetics as partof a multidisciplinary team. This setup broadly mimics the preclinical drugdiscovery structure found in the pharmaceutical industry, but with greaterfreedom to explore the higher-risk therapeutic targets commonly associated withneurological disorders.
"Akey aspect of successful preclinical discovery programs pursuing drugs forcentral nervous system (CNS) targets is the efficient and accurateidentification of compounds that exhibit favorable blood-brain barrier (BBB)permeation with little or no efflux transporter liabilities, and whose unboundconcentrations in the brain freely and rapidly equilibrate with those inplasma," states Dr. Thomas Bridges, a drug discovery scientist in drugmetabolism and pharmacokinetics (DMPK) within the VCNDD and the Department ofPharmacology at the VU Medical School. "To that end, our approach providesquantitative insight to compounds' brain distribution properties as a single,largely species-independent variable useful for establishing structure-activityrelationships (SAR), medicinal chemical optimization strategies and ultimately,to aid clinical candidate selection."
The throughput and data security advantages offered byautomated liquid handling are vital to the VCNDD's ADME screening workflow, andthe center uses a Tecan Freedom EVO 200 to provide routine processing of threeADME assays—an intrinsic clearance assay, a plasma protein binding assay usingRED (rapid equilibrium dialysis) plates and a cocktail-style cytochrome P450IC50 assay.
Dr. J. Scott Daniels, assistant professor of pharmacologyand director of DMPK at VCNDD, explains: "When I arrived at Vanderbilt, I saw agroup of well-meaning, hard-working drug metabolism scientists struggling withlimited resources. The pipetting systems we had in place weren't capable of thethroughputs and experimental integrity we needed, so we invested in a contemporaryliquid-handling platform which met the requirements of our workflow."
With throughput a key consideration, the VCNDD's Tecan unitis equipped with three independent robotic arms—an eight-channel pipetting arm,a 96-channel pipetting arm and a robotic gripper arm—allowing parallelprocessing of all three assays. Complete automation of these fundamental assaysis vital to streamline the DMPK group's workflow, requiring integration of anumber of additional devices onto the deck of the instrument. These includeincubators, incubated shakers and a microplate reader, providinghigh-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 thesystem 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 willeasily run up to 500 samples per day in the three assays Vanderbilt is mostinterested in. Often the system is set up during the day and then run from theafternoon into the evening unattended. Most customers like to run their systemdaily to ensure a good return on investment. As an example, the setting up ofan IC50 plate with compounds at different concentrations using theeight-channel pipetting arm would take around 10 to 15 minutes per plate."
Daniels summarizes: "From struggling with single pipettorson the bench, we have progressed to a fully automated linear platform withwhich we can perform several bread-and-butter assays every single week, drivingthe drug discovery pipeline and taking risks in novel targets in a way thatcompanies just cannot do given the current economic climate. By partnering withan experienced laboratory automation equipment manufacturer, we have been ableto make our facility into an efficient, high-throughput contemporary ADMEgroup."
Whatprogress has the VCNDD group reported to date? "To date, we have not had anydrug candidates in clinical trials," Conn admits. "However, we havereached the stage of achieving preclinical candidate status for three programs,each of which has been partnered with a major company for furtherdevelopment. While we cannot make firm predictions, if we are successfulin the preclinical development stage for these efforts, we could be ready toenter into Phase I clinical studies by the end of 2014.