Molecular Connection Reprint 2004 Vol 22 No 4 Molecular Connection Reprint 2004 n the view of James Kelly, PhD, president of Amphioxus Cell Technologies, the process of turning chemicals into pharmaceuticals has not kept pace with the mechanization and industrialization of drug discovery. “Drug discovery has changed dramatically over the past two decades, from an almost acciden tal process to a muc h more directed, biology- and chemistry-based process,” says Kelly. “Now, in its simplest embodiment, a compan y choos es a therap eutic area, finds a likely protein target and then starts screening chemicals for something that sticks. ” While high-throughput screening techniques are commonly associated with acceler ated workflows, in fact the initial screening phase represents only a step in the long drug development journey. “Much of the time of drug development is spent taking the hits and leads that come out of the screening programs and turning them into pharmaceuticals,” says Kelly. “A viable drug candidate has to have not onl y therapeutic e ffi- cacy but also a specific set of pharmaceutical qualities: it needs to be absorbed appropriate- ly, it has to last 24 to 48 hours, you have to be able to take 2 milligrams a day, and so on.” To keep up with the pace of modern screen- ing programs, Kelly’s Houston, Texas-based company has developed a high-throughput system for assessing the toxicology of com- pounds to the liver. Predicting toxicology—quickly “If you look at the percentage of drugs that fail for toxicity reasons, almost half are because of liver toxicity,” says Kelly. “We’ve developed a system that is based on a human liver cell line and replicates the properties of the hepato- cytes of the functional cell of the live r in vitro.” By culturing those cells in multi-well plates, Amphioxus can help companies test large numbers of compounds in short order. Compounds are incubated with cells and then measured for properties such as cell death and ATP content to assess their toxic liabilities. “These are simple, rapid assays that can be done in the same kind of time frame as screening,” says Kelly. “It gives you the ability to provide feedback to the chemist. ” Amphioxus works primarily with pharma- ceutical and biotech companies as well as some nutraceuticals and food supplement companies. “Where we come in is after they’ve screened their first or second set of compounds,” explains Kelly. “Then they can screen them in our assays to develop structure-toxicity relationships that correlate with their structure-activity relationships. We provide structure-toxicity relationship assessment early in the drug discovery process, so researchers don’t waste a lot of time on compounds that are going to fail as soon as they go into animals or humans. ” I The fight against liver toxicity Amphioxus employs MDL Assay Explorer to evaluate structure-toxicity relationships early in drug discovery Figure 1: Amphioxus employs MDL Assay Explorer and MDL ChemBio AE to capture, visualize andinterpret data from high-throughput toxicology screens.
